Lysosomal storage disorders result from a wide spectrum of genetic mutations affecting proteins integral to normal lysosomal function. Defects in no less than 50 proteins have been documented to cause lysosomal dysfunction, and new proteins linked to lysosomal disease continue to be discovered. Lysosomal diseases are known to affect many tissues and organs with most significantly impacting the brain, leading to severe cognitive impairment including dementia, ataxia, tremors and related motor system dysfunctions, blindness, deafness and other sensory impairments, psychotic episodes and seizures. This complex array of clinical features is reflected in a diversity of underlying molecular and cellular abnormalities, including ectopic dendritogenesis, neuroaxonal dystrophy, protein aggregation conditions including tauopathy, neurodegeneration, and so forth. We believe that this diversity of impact characteristic of storage diseases affecting brain is best explained by looking beyond the lysosome to broader abnormalities in endosomal, retrosomal, autophagosomal, and proteasomal systems, what we refer to as the 'Greater Lysosomal System'. Importantly, there is also increasing evidence that lysosomal diseases are not simply states of storage but are also states of deficiency, with failure to salvage degraded substrates from diseased lysosomes leading to shortages of critical precursors for other metabolic processes. Taken together, this new concept of lysosomal disease stresses the importance of viewing the lysosome and its processing streams not simply as a passive digestive process but rather as an integral player in far reaching cellular events, from signal transduction to homeostatic regulation. In order to advance understanding of lysosomal diseases affecting brain and to illuminate the role of the greater lysosomal system as a metabolic regulator in normal neurons, we propose a series of research aims to test hypotheses that attempt to explain the development of two of the most well documented but enigmatic features of many lysosomal diseases - ectopic dendritogenesis and neuroaxonal dystrophy. Delineation of these pathogenic pathways and the underlying role of the lysosomal system we believe will open the door to understanding, and treating, commoner neurodegenerative diseases that share similar features, from Fragile X and other dendritopathies to dementias like Alzheimer's disease.
While individually rare, lysosomal diseases as a whole have an incidence of 1 in 7,000 live births, and are therefore as a group one of the more common types of genetic disease. At least two thirds of these diseases affect brain and typically cause years to decades of intellectual and motor/sensory system decline, with severe consequences for both patients and families. Few treatments are available for lysosomal disorders affecting brain, and almost all are invariably fatal. To better develop therapies we need to know more about pathogenesis - how defects in what has been considered an inert, end-organelle ultimately causes such serious neurological demise. This proposal provides a new way of thinking about lysosomes and lysosomal diseases and presents a series of testable hypotheses that we believe will provide new insights into the role of the lysosomal system in neurons in both health and disease, including in common neurodegenerative disorders for which lysosomal compromise has been implicated (e.g., Alzheimer's and Parkinson's diseases).
|Sikora, Jakub; Leddy, Jennifer; Gulinello, Maria et al. (2016) X-linked Christianson syndrome: heterozygous female Slc9a6 knockout mice develop mosaic neuropathological changes and related behavioral abnormalities. Dis Model Mech 9:13-23|
|Praggastis, Maria; Tortelli, Brett; Zhang, Jessie et al. (2015) A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele. J Neurosci 35:8091-106|
|Kowalewski, BjÃ¶rn; Heimann, Peter; Ortkras, Theresa et al. (2015) Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III). Hum Mol Genet 24:1856-68|
|Vite, Charles H; Bagel, Jessica H; Swain, Gary P et al. (2015) Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease. Sci Transl Med 7:276ra26|
|Yang, Dun-Sheng; Stavrides, Philip; Saito, Mitsuo et al. (2014) Defective macroautophagic turnover of brain lipids in the TgCRND8 Alzheimer mouse model: prevention by correcting lysosomal proteolytic deficits. Brain 137:3300-18|
|Micsenyi, Matthew C; Sikora, Jakub; Stephney, Gloria et al. (2013) Lysosomal membrane permeability stimulates protein aggregate formation in neurons of a lysosomal disease. J Neurosci 33:10815-27|
|Xu, Miao; Liu, Ke; Swaroop, Manju et al. (2012) Î´-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. J Biol Chem 287:39349-60|
|Lieberman, Andrew P; Puertollano, Rosa; Raben, Nina et al. (2012) Autophagy in lysosomal storage disorders. Autophagy 8:719-30|
|Kollmann, K; Damme, M; Markmann, S et al. (2012) Lysosomal dysfunction causes neurodegeneration in mucolipidosis II 'knock-in' mice. Brain 135:2661-75|
|Cluzeau, Celine V M; Watkins-Chow, Dawn E; Fu, Rao et al. (2012) Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1. Hum Mol Genet 21:3632-46|
Showing the most recent 10 out of 26 publications