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Gene therapy has re-emerged as a potentially revolutionary treatment for familial and, eventually, sporadic, Alzheimer’s disease (Parts 2 and 3 of the Society for Neuroscience 2019 annual meeting series). While researchers are mulling over targets and strategies, what can they learn from gene therapies that are already in, or close to, clinical trials? Dozens of such therapies are being developed for lysosomal dysfunction, which is a feature of Alzheimer’s, Parkinson’s, and frontotemporal dementias (Whyte et al., 2017; Bonam et al., 2019). Could treatments for lysosomal storage disorders help scientists find ways to rid aging cells of proteins that lead to neurodegeneration?
It’s clear that cells need well-functioning lysosomes to maintain homeostasis. These acidic organelles are brimming with enzymes ready to break down washed-up proteins, lipids, and carbohydrates that end up inside lysosomes when they fuse with autophagosomes. The little sacs are deceptively complex: a typical lysosome contains around 60 different acid hydrolases alone, cathepsins being perhaps the best-known, plus granulins and other components (Marques and Saftig 2019). Lysosomes degrade Aβ, α-synuclein, and other proteins that accumulate in neurodegenerative disorders (Wang et al., 2012; Shacka et al., 2008). In the AD brain, lysosomes accumulate in neurons, and lysosomal proteins are even found in amyloid plaques (Nixon et al., 1992; Ihara et al., 2012). Since then, a steady clip of papers have documented the importance of lysosomal degradation in age-related neurodegeneration. Some implicated microglia (Paresce et al., 1997; Solé-Domènech et al., 2016). Most recently, single-cell analysis of AD brain tissue pinpointed upregulation of the lysosomal master transcription factor TFEB in astrocytes, where it regulates expression of as many as 10 AD genes (Nov 2019 news). Scientists believe that when lysosomes malfunction in subtle ways, proteins such as Aβ, α-synuclein, and TDP-43 can gradually build up in cells of the aging brain, increasing the chances they will form toxic oligomers or aggregates.
But when lysosomes take a severe hit, disease strikes already in childhood. Scientists know of at least nine forms of lysosomal storage disorder, including Niemann-Pick type C, Gaucher, Tay-Sachs, and Fabry diseases. Many have subtypes. The 14 known neuronal ceroid lipofuscinoses, seven mucopolysaccharidoses, five mucolipidoses, and two gangliosidoses are named after the type of molecule whose defective degradation in lysosomes leads to their buildup, i.e., storage.
Interestingly for gene-therapy developers, almost all these lysosomal storage diseases are monogenetic, caused by a pathogenic mutation in one or two gene copies encoding an enzyme or protein essential to lysosome function. They tend to start in infancy, childhood, or young adulthood and lead to physical deformities, dementia, motor defects, sometimes blindness, and often an early death (Kohlschütter et al., 2019). ...
