Endo-lysosomal dysfunction: a converging mechanism in neurodegenerative diseases
Introduction
Neurodegenerative diseases are often characterized by intracellular protein inclusions or extracellular protein aggregates. Failure of proper trafficking and degradation of these proteins could underlie neuronal and network dysfunction in these diseases. The lysosome system is one of the major cellular mechanisms for protein degradation, especially in long-lived, post-mitotic cells, such as neurons. Lysosomes serve as the hub for proteostasis (Figure 1). Protein substrates of extracellular and intracellular origin are delivered to lysosome through endocytic trafficking and autophagic pathways, respectively. Complex cross talk between these trafficking systems ensures proper sorting and degradation of the substrates. Dysfunction of various steps in this network can lead to insufficient clearance of pathogenic proteins, impaired membrane trafficking and signaling, and damage to the cell. Numerous studies in human genetics and model organisms support critical roles of lysosomal dysfunction in neurodegeneration. In this review, we focus on the role of endo-lysosomal dysfunction in three of the most common and devastating neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD) and frontotemporal dementia (FTD).
Section snippets
Alzheimer's disease
AD, the most common dementia, is characterized by extracellular amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT), consisting of hyperphosphorylated tau. The endo-lysosomal and autophagic networks are critical to maintain the homeostasis of Aβ and tau. Dysfunctions of this network are common in AD and result in abnormal lysosomal enzymatic activity and accumulation of autophagosomes and autolysosomes in the dystrophic neurites in AD brains [1]. More importantly, both familial mutations
Parkinson's disease
PD is the second most common late-onset neurodegenerative disease and is characterized by an accumulation of α-synuclein and mitochondrial dysfunction. Increasing evidence from genetics and model systems indicates that intracellular trafficking and endo-lysosomal/autophagic dysfunction is the primary cause in PD [28].
PTEN-induced putative kinase 1 (PINK1) and parkin, two key components for mitophagy, are associated with autosomal recessive parkinsonism, providing compelling evidence that
Frontotemporal dementia
FTD is the second most common cause of dementia in people under 65 years old. Pathologically, major FTD variants include inclusions of microtubule-associated protein tau or the TAR DNA-binding protein (TDP)-43, named FTLD-tau and FTLD-TDP, accordingly. FTD mutations of tau lead to increased tau accumulation and aggregation, where autophagic dysfunction plays an important role. Blocking autophagy increases tau accumulation [50], while enhancing autophagy lowers the levels of total and
Conclusion
Accumulating genetic evidence from GWAS has pointed to a critical role for the endo-lysosomal network in neurodegenerative diseases. Dysfunction of these genes and their pathways converges on impaired lysosomal degradation, leading to accumulation of pathogenic proteins. Besides, accumulation of intermediate vesicles containing undegraded proteins might lead to increased secretion and propagation of the pathogenic proteins, although the molecular mechanism remains elusive. Therapeutically,
Conflict of interest statement
Dr. Bahr is co-inventor on U.S. Patent 8,163,953 (Compounds for lysosomal modulation and methods of use) and on pending patents on compounds for treating Alzheimer's disease, mild cognitive impairment, and α-synucleinopathies.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Authors would like to thank Gary Howard to editorial assistance. The work is partially supported by NIH (R01AG051390 and U54NS100717 to L.G.); Consortium for Frontomtemporal dementia (to L.G.); Rainwater Foundation (to L.G.); Bluefield fellowship (to M.T.), NIH (K99 AG053439) to X.C., and the CART Organization (B.A.B.).
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