Lysosomes: The Achilles’ Heel of Neurons in Neurodegenerative Disease
Ralph A. Nixona,b
a, Center for Dementia Research, Nathan S. Kline Institute, 140 Old Orangeburg Road, Orangeburg NY 10962, USA.
b, Departments of Psychiatry and Cell Biology, New York University, 550 First Avenue, New York NY 10016, USA.
In most adult-onset neurodegenerative diseases, the protein(s) considered pathogenic accumulate only later in life implying a failure of protein quality control mechanisms as the brain ages. Autophagy, a lysosomal pathway for turnover of intracellular constituents, is one of the two major degradative systems in cells and is closely tied to mechanisms of cellular aging. Notably, it is the cell’s only means to turn over organelles, such as damaged mitochondria, and is also principally responsible for eliminating large protein aggregates. Because neurons are postmitotic, survive many decades, and exert quality control over large volumes of cytoplasm, they are more vulnerable than most cells to autophagy impairment. Indeed, mutations in > 30 genes functioning within the autophagic and endocytic pathways leading to lysosomes are known to be causal in familial forms of at least eight different neurodegenerative diseases, including forms of Alzheimer’s and Parkinson’s disease, ALS, and frontotemporal dementia
No disease better exemplifies the pathogenic importance of autophagy failure than Alzheimer’s disease (AD). A neuropathological hallmark of AD is the neuritic plaque comprised of dystrophic neurites that are filled principally with autophagic vacuoles (AVs) containing incompletely degraded substrates, including Aβ peptides. Such large accumulations of neuronal waste are rare among adult neurodegenerative diseases but very reminiscent of lysosomal storage diseases (LSDs). This massive AV buildup in the AD brain reflects primarily a failure of autophagy at the stage of autolysosomal clearance of autophagic substrates.
We find that the presenilins 1, 2 (PSEN1 or PSEN2) and amyloid precursor protein (APP) causing autosomal dominant early onset AD not only implicate Aß and APP-C99 in the disease pathogenesis, but also play critical roles within lysosomal pathways (autophagy and endocytosis), which are disrupted in AD. Mutations or duplication of these genes corrupt the lysosomal network by different mechanisms while also promoting ß-amyloidogenesis by accelerating endosomal activity and impeding lysosomal/autophagic clearance.
ysosomes require PSEN1 to assemble the vATPase proton-pump and loss of PSEN1 or PSEN2 function leads to defective lysosomal acidification and impaired autophagy. Besides impairing lysosomal acidification, APP mutations (or APP duplication as in Down Syndrome) and ApoE4 disrupt endosome signalling critical for cholinergic neuron survival. Lysosome pH regulates the large stores of calcium in lysosomes. The rise of lysosomal pH in AD models induces calcium efflux, which raises cytosolic calcium levels and activates calpain and protein kinases that mediate a cascade of AD-related pathological events. The ameliorative effects of therapeutic strategies targeting lysosome functions in AD models underscore the pathogenic importance of lysosomal dysfunction in AD.
Supported by the National Institute on Aging
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