Neuronal autophagy and neurodegenerative diseases

Abstract

Autophagy is a dynamic cellular pathway involved in the turnover of proteins, protein complexes, and organelles through lysosomal degradation. The integrity of postmitotic neurons is heavily dependent on high basal autophagy compared to non-neuronal cells as misfolded proteins and damaged organelles cannot be diluted through cell division. Moreover, neurons contain the specialized structures for intercellular communication, such as axons, dendrites and synapses, which require the reciprocal transport of proteins, organelles and autophagosomes over significant distances from the soma. Defects in autophagy affect the intercellular communication and subsequently, contributing to neurodegeneration. The presence of abnormal autophagic activity is frequently observed in selective neuronal populations afflicted in common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. These observations have provoked controversy regarding whether the increase in autophagosomes observed in the degenerating neurons play a protective role or instead contribute to pathogenic neuronal cell death. It is still unknown what factors may determine whether active autophagy is beneficial or pathogenic during neurodegeneration. In this review, we consider both the normal and pathophysiological roles of neuronal autophagy and its potential therapeutic implications for common neurodegenerative diseases.

Figure 1

The basic and pathogenic role of neuronal autophagy. Neurons have highly specialized structures for intercellular communication, which typically include the soma, axon, dendrites and synapses. In the soma, the central region of the neuron containing the nucleus, basal levels of autophagy, including macroautophagy, mitophagy and chaperone-mediated autophagy (CMA), occur to maintain normal cellular homeostasis. The axon, a specialized structure to conduct nerve impulses, transfers proteins and organelles over significant distances by axoplasmic transport. Axotomy and excitotoxic insult trigger the accumulation of autophagosomes in dystrophic axonal swellings. Autophagic vaculoes (AVs) have also been observed in dysfunctional axons in alzheimer's disease (AD), parkinson's disease (PD) and huntington's disease (HD). Synapse, the region of contact where a neuron transferring information to another cell, represents a region of high energy demand and protein turnover; They contain abundant mitochondria and polyribosomes. Autophagy is known to play an important role in synapse development as autophagy is induced in response to many developmental and environmental cues. Thus, autophagy may play an important role in the synapse growth and plasticity required for learning and memory.

Figure 2

Disease causing proteins affecting various types of autophagy in common neurodegenerative diseases. Familial forms of the common neurodegenerative diseases, such as AD, PD, HD and ALS, are caused by gene mutations, which affect different types and steps of autophagy. AD is characterized by the pathogenic accumulation of amyloid plaques consisting of β-amyloid (Aβ) peptides generated by proteolytic cleavage of amyloid precursor protein (APP). AVs are a major reservoir of intracellular Aβ in the brain. Mutant presenilin 1 (PS1) impairs autophagosome clearance, resulting in enhanced Aβ accumulation in AD. PD is characterized by the presence of Lewy bodies, the intracytoplasmic inclusions containing α-synuclein, which is degraded by macroautophagy and CMA. The inhibition of CMA leads to an accumulation of soluble high molecular weight and detergent-insoluble species of α-synuclein and the inhibition of macroautophagy also leads to the accumulation of wild type α-synuclein. Mitochondrial dysfunction has been implicated in the pathogenesis of PD. PINK1 and parkin mediate the removal of mitochondria by mitophagy, of which mutations result in the accumulation of impaired mitochondria. HD is characterized by the presence of inclusion bodies composed of the N-terminal fragment of mutant Htt, which is associated with the primary defect in the ability of autophagic vacuoles to recognize cytosolic cargo. Mutations in the SOD1gene underlie 20% of familial ALS cases. Agents promoting autophagy, such as lithium and rapamycin, help autophagic clearance of mutant SOD1.

Figure 3

PINK1 and parkin-mediated mitophagy. In the current model of the PINK1/parkin-mediated mitophagy, PINK1, implicated in familial PD, is normally maintained at low levels on mitochondria by voltage-dependent proteolysis, which is mediated by the mitochondrial presenilin-associated rhomboid-like protein (PARL) present in the inner mitochondrial membrane. In the absence of PARL, the constitutive degradation of PINK1 is inhibited and a 60-kD form of PINK1 is stabilized inside mitochondria. When the mitochondrial membrane potential is dissipated, PINK1 accumulates as a 63-kD full-length form in the outer mitochondrial membrane. Thus, accumulation of mitochondrial damage by gene mutations or carbonyl cyanide m-chloro phenyl hydrazone (CCCP), a mitochondrial uncoupling agent, facilitates the rapid accumulation of PINK1 and the subsequent PINK1 accumulation in the mitochondria recruits parkin to ubiquitinate VDAC (and/or mitofusin) on the mitochondrial outer membrane, which becomes a target for mitophagy. The ubiquitin-binding adaptor p62 (also known as sequestosome 1) recruits ubiquitinated cargo into autophagosomes by binding to LC3.