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Pdf file on Oxford 
The lysosome and neurodegenerative diseases
Lisha Zhang, Rui Sheng, and Zhenghong Qin*
Department of Pharmacology and Laboratory of Aging and Nervous Diseases,
*Correspondence address. Tel/Fax: +86-512-65880406;
E-mail: [email protected]
It has long been believed that the lysosome is an
important digestive organelle. There is increasing evidence that the lysosome
is also involved in pathogenesis of a variety of neurodegenerative diseases,
including Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease, and amyotrophic lateral
sclerosis. Abnormal protein degradation and deposition induced by lysosomal
dysfunction may be the primary contributor to age-related neurodegeneration. In
this review, the possible relationship between lysosome and various
neurodegenerative diseases is described.
Keywords lysosome;
neurodegenerative diseases; Alzheimer’s disease; Parkinson’s disease;
Huntington’s disease
Received: December 16, 2008 Accepted: April 07, 2009
Introduction
Lysosomes are acidic, membrane-bound organelles in which .50 acid hydrolases are stored and perform the catabolism of the cells at
an optimum pH in the range of 4.6–5.0 [1]. Lysosomes are
responsible for the degradation of macromolecules derived from the
extracellular space through endocytosis or phagocytosis, as well as from the
cytoplasm through autophagy. Lysosomal storage disorders (LSDs) are a group of
genetic disorders that result from a disorder of lysosomal catabolism, due to
defects in specific hydrolytic enzyme, activator protein or cofactor, transport
protein or enzyme required for the correct processing of other lysosomal
proteins, such as mucopolysaccharidoses, sphingolipidoses, mucolipidoses,
lipidoses, glycoproteinoses, glycogenosis, lipofuscinoses and
mucopolysaccharidoses.
Neurodegenerative diseases are characterized by progressive dysfunction
and death of cells that frequently affect specific neural systems, including
Alzheimer’s
disease (AD), Parkinson’s disease (PD), amyotrophic
lateral sclerosis, spinal cerebellar ataxias, and spinal muscular atrophy [2].
The aim of the present review is to describe the relationship between lysosome
and neurodegenerative diseases.
Structure and Function of Lysosomes
Lysosomes and cathepsins
According to its physiological function at different stages, lysosome can be
divided into the primary lysosome, the secondary lysosome, and the residual
body. Primary lysosomes are membrane-bound intracellular organelles that
contain a variety of hydrolytic enzymes, including acid phosphatase,
glucuronidase, sulfatase, ribonuclease, and collagenase. These enzymes are
synthesized in the rough endoplasmic reticulum and then packaged into vesicles
in the Golgi apparatus. Primary lysosomes fuse with membrane-bound vacuoles
that contain material to be digested, forming secondary lysosomes. Residual
bodies contain only indigestible or slowly digestible materials and within
which enzymatic activities have become virtually exhausted. The main class of
lysosomal proteases is represented by the cathepsin which is derived from the
Greek term meaning ‘to digest’ [3]. Cathepsins are subdivided
into three subgroups according to the amino acids of their active sites that
confer catalytic activity: cysteine (cathepsins B, C, F, H, K, L, N, O, S, T,
U, W, and X), aspartyl (cathepsins D and E), and serine cathepsins (cathepsins
A and G).
Cathepsins are synthesized in membrane-bound ribosomes as N-glycosylated
precursors and are transferred into the endoplasmic reticulum and later into
the Golgi complex. During transport to the Golgi complex, procathepsins acquire
modification of their carbohydrate moieties, which includes the formation of
the mannose 6-phosphate (M6P) residues. After binding to M6P-specific
receptors, the enzyme–receptor complexes
exit the trans-Golgi network in clathrin-coated vesicles and transport to the
late endosomes [4]. Upon fusion with the late endosomes, the dissociation of
ligands occurs. When the receptors are recycled back to the Golgi apparatus,
the major parts of enzymes reach lysosomes through this targeting pathway. Subsequently,
the active cathepsin can be produced after proteolytic removal of the
propeptide in the acidic environments of late endosomes or lysosomes. The last
step is accompanied by the actions of several proteases, such as pepsin,
neutrophil elastase, and various cysteine proteases [5]. The cathepsin activity
is regulated by several mechanisms including regulation of synthesis, zymogen
processing, endogenous inhibitors (e.g. stefins and cystatins for cysteine
cathepsins), and pH stability [6,7]. The cathepsins play important roles in
many physiological processes such as protein degradation, antigen presentation,
bone resorption, and hormone processing [6]. Felbor et al. [8] revealed that cathepsin B2/2/L2/2 mice showed a degree of brain atrophy not previously seen in mice. These
results demonstrated that cathepsins B and L were essential for maturation and
integrity of the postnatal central nervous system (CNS) and that the two
proteases compensated for each other in vivo [8].
Lysosomes and apoptosis
Apoptosis is the most common form of physiological cell death in
multicellular organisms. Apoptosis signaling is classically composed of two
principle pathways. One is a direct pathway from death receptor (CD95, TNF-R1,
and TRAIL-R1/TRAIL-R2 [9]) ligation to caspase cascade activation and cell
death. Death receptor ligation triggers recruitment of the precursor form of
caspase-8 to a death-inducing complex, through the adaptor protein FADD, which
leads to caspase-8 activation. The other pathway triggered by stimuli such as
drugs, radiation, infectious agents, and reactive oxygen species is initiated
in mitochondria. After cytochrome c is released into the cytosol from the mitochondria, it binds to Apaf1 and
ATP, which then activate caspase-9.
Under either physiological or pathological conditions, apoptosis is mostly
driven by interactions among several families of proteins, i.e. caspases, Bcl-2
family proteins, and inhibitor of apoptosis proteins [10]. Besides the
caspases, lysosomal proteases such as cathepsins D, B, and L have been shown to
act as mediators of apoptosis in a number of cell systems [11–14]. Increased expression or activity of cathepsin D has been observed in
apoptotic cells after activation of Fas/APO-12 and after exposure to oxidative
stress or adriamycin [15]. Results show that p53 has two binding sites located
at the cathepsin D promoter gene and that cathepsin D participates in
p53-dependent apoptosis. Cathepsin D showed augmented activity soon after it
was released and that was accompanied by increased levels of p53 protein, a
cathepsin D transcription factor [16]. Therefore, the mechanism responsible for
increase in cathepsin D activity might be an effect of increased synthesis
regulated by p53. Cathepsin B has also been implicated in the activation of the
pro-inflammatory caspases-1 and -11, and the cleavage of Bcl-2 family member
Bid which may lead to cytochrome c release from the mitochondria and subsequent caspase activation [17].
Ishisaka et al. [13] revealed the participation of cathepsin L in a direct activation of
caspase-3 [18].
It is known that lysosome is involved not only in apoptosis but also in
other types of cell death. The permeabilization of the lysosome has been shown
to initiate a cell death pathway in specific circumstances. Lysosomal membrane
permeabilization (LMP) causes the release of cathepsins and other hydrolases
from the lysosomal lumen to the cytosol. LMP is a potentially lethal event
because the ectopic presence of lysosomal proteases in the cytosol causes
digestion of vital proteins and the activation of additional hydrolases
including caspases. This latter process is usually mediated indirectly, through
a cascade in which LMP causes the proteolytic activation of Bid (which is
cleaved by the two lysosomal cathepsins B and D). The Bid activation then
induces mitochondrial outer membrane permeabilization, resulting in cytochrome c release and
apoptosome-dependent caspase activation [19]. However, massive LMP often
results in cell death without caspase activation, which may adopt a
subapoptotic or necrotic appearance. Moreover, the pro-apoptotic Bcl-2 family
member Bax can translocate from the cytosol to lysosomal membranes and induce
LMP [20].
Lysosomes and autophagy
The lysosomal system is responsible for the degradation of several classes
of macromolecules and for the turnover of organelles by several mechanisms
collectively known as autophagy.
Autophagy is a regulated process of degradation and recycling of cellular
constituents, participating in organelle turnover and in the bioenergetic
management of starvation. This term embraces several different mechanisms:
macroautophagy, microautophagy, chaperone-mediated autophagy (CMA), and
crinophagy [21]. In macroautophagy, the cytoplasm is sequestered into
double-membrane structures known as autophagosomes that fuse with endosomes and
lysosomes. After fusion, the vacuolar materials are degraded and recycled. In
microautophagy, small cytosolic portions are internalized via lysosomal
invaginations, and proteins are continuously degraded in the lumen of this
organelle even under resting conditions. In contrast with these bulk autophagy
pathways, a third lysosomal degradation pathway is CMA. In CMA, specific
cytosolic proteins are transported into lysosomes via a molecular chaperone/
receptor complex. Different from the other lysosomal degradation pathways,
vesicular traffic is not involved in CMA. Functionally, secretory lysosomes are
unusual, in that they serve both as a degradative and as a secretory
compartment [22]. Some studies have clearly demonstrated that autophagy has a
greater variety of physiological and pathophysiological roles than expected,
such as starvation adaptation, intracellular protein and organelle clearance,
development, anti-aging, elimination of microorganisms, cell death, tumor
suppression, and antigen presentation [23]. Autophagy may also be involved in
neurodegenerative diseases, as recent studies reported increased autophagy in
AD and PD.
Lysosome and Neurodegenerative Diseases
Lysosome and AD
AD is a progressive neurodegenerative disorder characterized by cognition
and memory impairment. AD brains are characterized by two pathological
hallmarks in the cerebral cortex and hippocampus: senile plaques (SPs),
consisting of deposits of b-amyloid peptide (Ab), and neurofibrillary
tangles (NFTs), composed of an abnormally phosphorylated form of the
cytoskeleton-associated protein Tau. The pathological accumulation of Ab and
hyperphosphorylation of Tau may develop concomitantly within synaptic terminals
and then induce loss of synapses, which is considered to be closely correlated
with the cognitive decline in AD [24].
Lysosomal dysfunction and Ab. The identification of Ab as the major component
of the SPs leads to the idea that deposition of Ab may induce neuronal
dysfunction and cell death, which is one of the primary causes of AD [25]. The
two most common isoforms of Ab are Ab40 and Ab42, which vary by the
length of the C-terminals [26].
Ab is derived from b-amyloid precursor protein (APP) by proteolytic cleavage with a-, b-, and g-secretases. a-Secretase cuts in the
middle of the part of APP which will become Ab and therefore blocks Ab production, whereas b– and g-secretases cleave the
amino and C-terminals of the Ab sequence,
respectively, promoting Ab formation [27]. There
are at least two cellular pathways (subcellular locations) proposed for Ab production, namely the
secretory pathway and the endosomal lysosomal pathway. b-Secretase (b-APP-cleaving enzyme)
is a type-1 transmembrane aspartyl protease, mainly localized in endosomes and
lysosomes [28], so it is mainly involved in endosomal–lysosomal pathway, but not the secretory pathway. The g-secretase often
resides in a high molecular weight multimeric protein complex composed of at
least four core components, i.e. presenilin 1 or 2 (PS1 or PS2), nicastrin,
anterior pharynx defective-1, and presenilin enhancer-2 [29]. Its activity has
been demonstrated in both the autophagosome and the lysosome, so Ab could be produced in
these compartments as well. In addition, chronic source of soluble, exogenous Ab peptides in the blood
can even cross a defective blood–brain barrier and
interact with neurons in the brain and then accumulate within these cells [30].
In 1990, many researches showed the close relationship between lysosomal
dysfunction and morphology in AD. Lysosomal dysfunction may be the earliest
histological change in AD [31]. Amyloid plaques are full of active lysosomal
hydrolases, implying that plaques may originate from lysosomal rupture.
Cathepsins D and E (intracellular aspartyl proteases) are considered to
influence Ab peptides generation within the endosomal–lysosomal pathway because they exhibit b– and g-secretase
like-activity [32]. For this reason, the endosomal–lysosomal pathway is a site for cleavage of the APP into smaller b-amyloid-containing
peptides, which are then degraded by cathepsins. Inhibition of cathepsins
activity causes a rapid and pronounced build-up of potentially amyloidogenic
protein fragments [33]. On the other hand, a failure to degrade aggregated Ab1–
Lysosomal dysfunction and Tau. Tau, a
microtubule-associated phosphoprotein, plays an important role in maintaining
neuronal morphology. Tau protein is normally localized in the neuronal axon,
where it promotes microtubule assembly and stabilizes microtubules. However,
under pathological conditions, such as AD, hyperphosphorylated Tau accumulates
in neurons in the form of paired helical filaments (PHFs) [37], which
subsequently form NFTs. PHF-bearing neurons are abundant in the areas in which
neuronal loss is found in AD [38]. Experimentally induced lysosomal dysfunction
triggers the development of characteristic features of the aged human brain.
These include proliferation of endosomes–lysosomes, hyperphosphorylation of Tau, production of Tau protein
fragments resembling those found in NFTs, and the accumulation of 16–30 kDa proteins that incorporate the amyloid sequence [39]. Bi et al. [40] found that the
novel cathepsin D inhibitors block the formation of hyperphosphorylated Tau
fragments in hippocampus of AD. Moreover, recent evidence showed that
autophagic-lysosomal system also plays a role in the clearance of Tau, whereas
dysfunction of this system results in the formation of Tau insoluble aggregates
in lysosomes [41].
Indeed, Tau is present in phosphorylated and aggregated form not only in
AD but also in other pathological situations. Frontotemporal dementia with PD
linked to chromosome-17 (FTDP-17) is an autosomal-dominant disease with variable
clinical and neuropathological features. Neuropathological changes include
frontotemporal atrophy, sometimes with atrophy of the basal ganglion,
substantia nigra, and amygdala. FTDP-17 is caused by mutations in the gene for
Tau. To investigate how Tau alterations provoke neurodegeneration, Lim et al. [42] generated
transgenic mice expressing human Tau with four tubulin-binding repeats and
three FTDP-17 mutations: G272V, P
Lysosome and Huntington’s disease
Huntington’s
disease (HD) is an autosomal-dominant neurological disease characterized by
involuntary movement accompanied by cognitive impairment and emotional
disturbance. The most striking pathological feature of HD is atrophy, neuronal
loss, and astrogliosis in the neostriatum [43]. Although multiple populations
of striatal neurons are affected in HD, the spiny projection neurons containing
g-aminobutyric acid and substance P or enkephalin are most vulnerable.
Other less severely affected brain regions include cerebral cortex and thalamic
nuclei.
Like other neurological diseases including AD and PD, HD is also a
protein-misfolding disease. It is caused by a CAG trinucleotide repeat
expansion in the huntingtin gene, which results in an expansion of the
polyglutamine tract in the amino N-terminus of the huntingtin protein. Normal
individuals have ≤35 CAG repeats, whereas HD is caused by ≥36 repeats. The increase in the length of polyglutamine tract alters
biochemical and biophysical properties of proteins. As a result, these proteins
are prone to form stable b-sheet structure and assemble into
oligomers. The bio-hallmark of mutant huntingtin is the formation of
intranuclear inclusions and cytoplasmic aggregates in neurons in vulnerable
brain areas. Expression of mutant huntingtin in cultured cells also causes the
formation of intranuclear inclusions and aggregates in the cytoplasm. The
inclusions and aggregates are usually formed by small N-terminal huntingtin
fragments and are co-localized with other cellular proteins involved in
proteolysis, vesicle trafficking, and protein degradation [44]. The formation
of huntingtin aggregates and intranuclear inclusions has been proposed to play
a role in HD pathogenesis. Huntingtin protein (htt) cleavage may be a crucial,
causal event in the pathogenesis of HD, and the most obvious consequence of htt
cleavage is the release of N-terminal fragments containing the polyglutamine
tract [45]. Fragments containing polyglutamine tracts of normal size do not
accumulate within cells. In contrast, fragments containing expanded
polyglutamine tracts may fold into a structure that resists threading into the
proteasome core, resulting in delayed clearance and accumulation within the cytoplasmic
or nuclear compartment of the cell [46]. Therefore, the production and
accumulation of N-terminal huntingtin (N-htt) fragments may be critical in the
pathogenic process.
Huntingtin processing occurs through proteasome and endosomal–lysosomal pathways. Caspase-3 and calpain are proteases that cleave htt to
produce stable N-htt fragments [47,48]. N-terminal mutant huntingtin (N-mhtt)
fragments cause cell death in vitro. Mutant N-htt fragments accumulate in HD neurons because they resist
degradation by the proteasome [49–51]. In addition, a
decline in proteasome function with age may contribute to mutant N-htt fragment
accumulation [52]. Yet, mutant htt expression or proteasome inhibition in vitro can increase levels of
lysosomal proteases [49,50,53]. Degradation of truncated huntingtin by an
autophagic mechanism was reported [50,54]. It was found that inhibiting
autophagy with 3-methyladenine increased accumulation of mutant huntingtin and
huntingtin aggregates, whereas stimulating autophagy with rapamycin reduced
both huntingtin accumulation and huntingtin aggregates. Our recent studies
found that autophagy was involved in activation of cathepsins and caspase-3
induced by overexpression of huntingtin. Both cathepsin D and L levels
increased upon expression of huntingtin.
In vitro studies revealed that wilt-type huntingtin was efficiently degraded by
cathepsin D, whereas mutant huntingtin was more resistant to cathepsin D [50].
Biochemical analysis of lysates from HD patient brain suggests that mutant htt
is more resistant to degradation than wild-type htt [46]. Autophagy may
stimulate huntingtin cleavage and degradation through activation of caspase-3
and cathepsin D. The autophagic mechanism may also contribute to the formation
of huntingtin bodies [47]. Increases in cathepsin D and H activity have been
found in affected areas in HD brain [48].
Lysosome and PD
PD is a neurodegenerative disorder characterized by resting tremor,
rigidity, hypokinesia, and postural instability. It is caused by the degeneration
of dopaminergic (DA) neurons in the substantia nigra. The pathogenic hallmark
of PD is the accumulation and aggregation of a-synuclein (a-syn) in susceptible
neurons. The brain regions that are affected in PD exhibit neuronal
intracytoplasmic inclusions that are termed Lewy bodies (LBs) when they are
present in cell bodies and Lewy neurites in neuron processes. These inclusion
bodies are particularly rich in aggregated a-syn, but also contain
numerous other proteins, including components of the ubiquitin–proteasome system, molecular chaperones, and lipids [55–57]. The syn family of peptides is a group of presynaptic proteins with
three members: a-, b-, and g-syn [58,59]. These pro-proteins are characterized by natively unfolded
structures with highly conserved N termini and divergent C-terminal acidic
regions [60]. Importantly, a-syn is distinct from other members of the
syn family in that it possesses a highly hydrophobic central region that has
been identified as a non-amyloid-b component (NAC) of AD
amyloid [61]. a-Syn is normally enriched in nerve terminals involved in synaptic
function. During normal aging and in PD, levels of natively folded a-syn increase in the
cytoplasm of substantia nigra neurons [62]. a-Syn is likely to play
a key role in the development of PD as well as other synucleinopathies. In
animal models, overexpression of full-length or C-terminally truncated a-syn has been shown to
produce PD pathology. In vitro experiments, using either recombinant or endogenous a-syn as substrates and
purified cathepsin D or lysosomes, have demonstrated that cathepsin D degrades a-syn very efficiently
and that limited proteolysis resulted in the generation of C-terminally
truncated species. Knockdown of cathepsin D in cells overexpressing wildtype a-syn increased total a-syn levels by 28%.
And pepstatin A (the inhibitor of cathepsin D) completely blocked the
degradation of a-syn in purified lysosomes. Furthermore, lysosomes isolated from cathepsin
D knockdown cells showed a marked reduction in a-syn degrading
activity, indicating that cathepsin D is the main lysosomal enzyme involved in a-syn degradation [63].
Recently, the colleagues of our lab observed the nuclear translocation of
cathepsin L in nigral DA neurons. Cathepsin L may contribute to cell cycle
arrest and death of DA neurons through its nuclear translocation [64].
a-Syn and ubiquitin are among the major components of LBs [65,66],
suggesting again an association with PD pathogenesis. Some studies indicate
that two separate a-syn mutations, A53T and A30P, are responsible for certain rare familial
forms of the disease. Wild-type a-syn was selectively translocated into
lysosomes for degradation by the CMA pathway. The pathogenic A53T and A30P a-syn mutants bound to
the receptor for this pathway on the lysosomal membrane, but appeared to act as
uptake blockers, inhibiting both their own degradation and that of other
substrates [67]. Stable PC12 cell lines expressing mutant but not wild-type a-syn show disruption
of the ubiquitin-dependent proteolytic system, marked accumulation of
autophagic–vesicular structures, and impairment of lysosomal hydrolysis and
proteasomal function [68].
In contrast to a-syn, b-syn may be neuroprotective, because this molecule has a natural deletion in
the middle of the NAC-associated region. Supporting this notion,
neuropathological features of a-syn transgenic (tg) mice, such as
formation of LBs and motor function deficits [69], are significantly
ameliorated in a– and b-syn bigenic mice compared with a-syn single tg mice [70,71]. Furthermore, b-syn directly
inhibited aggregation and proto-fibrillar formation of a-syn under cell-free
conditions [70,72,73]. Although g-syn also inhibits a-syn aggregation [72],
the role of this molecule in neuroprotection is not completely clear.
Lysosome and Niemann–Pick disease type C The LSDs are caused by the defective
activity of lysosomal proteins, which results in the intra-lysosomal
accumulation of non-degraded metabolites. Today, over 30 kinds of diseases in
LSDs have been found. LSDs can be grouped according to characterization of the
defective enzyme or protein [74]. Niemann–Pick C (NPC) is a very important type of LSDs. NPC belongs to the Niemann–Pick disease group of lipidoses along with Niemann–Pick types A and B. NPC is different from type A or B. NPA represents a
classical acute neuropathic form of the disease, whereas NPB is a chronic form
without nervous system involvement. In types A and B, the main problem in the
body is the complete or partial lack of an enzyme called sphingomyelinase.
Although clinically similar to NPA and NPB, NPC’s sphingomyelinase is functional [75].
NPC is a neurovisceral lysosomal lipid storage disorder of autosomal recessive
inheritance characterized at the cellular level by accumulation of unesterified
cholesterol and glycolipids in the endosomal–lysosomal system. The disease is often diagnosed in early childhood, with
patients typically displaying cerebellar ataxia, difficulty in speaking and
swallowing, and progressive dementia. In NPC, cholesterol and glycolipids have
varied roles in the cell. Cholesterol is normally used to either build the cell
or forms a complex molecule called an ester. In the case of an individual with
NPC, there are large amounts of cholesterol that are not used as a building
material and also do not form esters. This cholesterol begins to accumulate
within the cells throughout the body, especially in the spleen, liver, bone
marrow, and brain. These unprocessed cholesterol as well as glycolipids stored
in the brain cause progressive neurological damage.
Mutations in either of the two human NPC genes, NPC1 and NPC2, cause a
fatal neurodegenerative disease associated with abnormal cholesterol accumulation
in cells. Approximately 95% of the NPC cases are caused by genetic mutations in
the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2
gene, referred to as type C2 [76]. The NPC1 gene produces a protein that is
located in membranes inside the cell and is involved in the movement of
cholesterol and lipids within cells [77]. A deficiency of this protein leads to
the abnormal build-up of lipids and cholesterol within cell membranes. The NPC2
gene produces a protein that binds and transports cholesterol [78,79], although
its exact function is not fully understood. The increased cholesterol in NPC
late endosomes and lysosomes interferes with transport of proteins between
these compartments [80]. The lysosomal hydrolase, cathepsin B, was upregulated
in NPC cells. Both cathepsins B and D can function as b-secretase enzymes and
are partially mislocalized to early endosomes in NPC [81,82].
In this review, we are most interested in the close relationship between
NPC and AD. Although NPC differs in major respects from AD, intriguing
parallels exist in the cellular pathology of these two diseases, including
neurofibrillary tangle formation, prominent lysosome system dysfunction, and
influences of apolipoprotein E4 genotype [83]. These findings suggest that
lipids are playing important roles in the development of neurodegenerative
diseases. So, it can demonstrate that the widely used cholesterol-lowering
drugs simvastatin and lovastatin reduce intracellular and extracellular levels
of Ab1–42 peptides in primary cultures of hippocampal neurons and mixed cortical
neurons [84]. Furthermore, it evidences that dysfunction of the lysosomal in
brain plays an important role in protein deposition diseases.
Concluding Remarks
In general, alterations in the lysosme degradation have been described in
normal brain aging and in age-related neurodegenerative diseases including AD,
HD, PD, and NPC. Cathepsins are now recognized as having more complex functions
than simply being garbage disposers, and their imbalance during aging and
age-related diseases may provoke deleterious effects on CNS neurons (Table 1). Lysosomes may be ‘bioreactor’ sites for the unfolding and partial degradation of membrane
proteins or their precursors that subsequently become expelled from the cell,
or are released from dead cells and accumulate as pathological entities. The
growing understanding of consequences of their age-related changes in neurons
could contribute to the development of therapeutic interventions in massive neurodegeneration
associated with these age-related diseases.
Funding
This work was supported by the grants from the Natural Science Foundation
of Jiangsu Province (BK 2007548), the Natural Science Foundation of China
(30801391), and Suzhou Social Progress Foundation (SS0729) and
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