Therapeutic induction of autophagy to modulate neurodegenerative disease progression

Abstract

There is accumulating evidence that aggregating, misfolded proteins may have an impact on autophagic function, suggesting that this could be a secondary pathological mechanism in many diseases. In this review, we focus on the role of autophagy in four major neurodegenerative diseases: Alzheimer disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and amyotropic lateral sclerosis.

Figure 1

A schematic of autophagy showing stages disrupted in selected neurodegenerative diseases. In starvation conditions, or growth factor deprivation, autophagy is stimulated due to mammalian target of rapamycin (mTOR) inhibition. Autophagy begins with the formation of a cup-shaped double-membrane structure, termed a phagophore. This is followed by membrane elongation and fusion to form a complete autophagosome, engulfing mutant and/or aggregate-prone proteins such as excess alpha-synuclein from the cytoplasm. Autophagosomes are then trafficked along microtubule tracks via dynein motors towards the lysosomes where autophagosome-lysosome fusion occurs, generating an autophagolysosome. Excess alpha-synuclein disrupts autophagic initiation in Parkinson's disease (PD). In amyotropic lateral sclerosis (ALS), mutations in the dynein/dynactin complex inhibit autophagosome trafficking to lysosomes. Inefficient autophagosome-lysosome fusion and defects in lysosomal acidification contributes to pathogenesis in forms of Alzheimer's disease (AD).