Elsevier

Current Opinion in Neurobiology

Volume 48, February 2018, Pages 52-58
Current Opinion in Neurobiology

Endo-lysosomal dysfunction: a converging mechanism in neurodegenerative diseases

https://doi.org/10.1016/j.conb.2017.09.005Get rights and content

Highlights

  • Multiple genes for AD, PD and FTD are involved in the endo-lysosomal pathways.

  • Dysfunction of endo-lysosomal pathways impairs degradation of pathogenic proteins.

  • Key components in the endo-lysosomal machinery may be therapeutic targets.

Endo-lysosomal pathways are essential in maintaining protein homeostasis in the cell. Numerous genes in the endo-lysosomal pathways have been found to associate with neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and frontotemporal dementia (FTD). Mutations of these genes lead to dysfunction in multiple steps of the endo-lysosomal network: autophagy, endocytic trafficking and lysosomal degradation, resulting in accumulation of pathogenic proteins. Although the exact pathogenic mechanism varies for different disease-associated genes, dysfunction of the endo-lysosomal pathways represents a converging mechanism shared by these diseases. Therefore, strategies that correct or compensate for endo-lysosomal dysfunction may be promising therapeutic approaches to treat 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.).

References (67)

  • A.M. Pickrell et al.

    The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease

    Neuron

    (2015)
  • D. Waschbusch

    LRRK2 transport is regulated by its novel interacting partner Rab32

    PLOS ONE

    (2014)
  • C.F. Bento et al.

    The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway

    Nat Commun

    (2016)
  • P. Ejlerskov

    Tubulin polymerization-promoting protein (TPPP/p25alpha) promotes unconventional secretion of alpha-synuclein through exophagy by impairing autophagosome-lysosome fusion

    J Biol Chem

    (2013)
  • J.R. Mazzulli

    Activation of beta-glucocerebrosidase reduces pathological alpha-synuclein and restores lysosomal function in Parkinson's patient midbrain neurons

    J Neurosci

    (2016)
  • V. Schaeffer

    Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy

    Brain

    (2012)
  • J. Ugolino

    Loss of C9orf72 enhances autophagic activity via deregulated mTOR and TFEB signaling

    PLoS Genet

    (2016)
  • H. Lui

    Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation

    Cell

    (2016)
  • L.S. Whyte et al.

    Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?

    J Neurochem

    (2017)
  • R. Sannerud

    Restricted location of PSEN2/gamma-secretase determines substrate specificity and generates an intracellular Abeta pool

    Cell

    (2016)
  • K. Ando

    Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains

    Acta Neuropathol

    (2013)
  • K. Ando

    Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease

    Neurobiol Dis

    (2016)
  • F. Pickford

    The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice

    J Clin Invest

    (2008)
  • P. Nilsson

    Abeta secretion and plaque formation depend on autophagy

    Cell Rep

    (2013)
  • E. Morel

    Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system

    Nat Commun

    (2013)
  • Q. Xiao

    Neuronal-targeted TFEB accelerates lysosomal degradation of APP, reducing Abeta generation and amyloid plaque pathogenesis

    J Neurosci

    (2015)
  • V.A. Polito

    Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB

    EMBO Mol Med

    (2014)
  • A. Magini

    Abnormal cortical lysosomal beta-hexosaminidase and beta-galactosidase activity at post-synaptic sites during Alzheimer's disease progression

    Int J Biochem Cell Biol

    (2015)
  • S. Choi

    Lysosomal enzyme glucocerebrosidase protects against Abeta1-42 oligomer-induced neurotoxicity

    PLOS ONE

    (2015)
  • C. Wang et al.

    Cathepsin B degrades amyloid-beta in mice expressing wild-type human amyloid precursor protein

    J Biol Chem

    (2012)
  • M. Torres

    Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus

    Mol Neurodegener

    (2012)
  • S. Cermak

    Loss of cathepsin B and L leads to lysosomal dysfunction, NPC-like cholesterol sequestration and accumulation of the key Alzheimer's proteins

    PLOS ONE

    (2016)
  • D.S. Yang

    Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits

    Brain

    (2011)
  • Cited by (0)

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