Regional lysosomal malfunction underlies the selectivity of alpha-synuclein neurodegeneration [electronic resource].

Malkus, Kristen Ashley.
174 p.
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Mode of access: World Wide Web.
Dysfunction of protein homoeostasis has been implicated in the pathogenesis of a diverse array of neurodegenerative disorders. However, each neurodegenerative disease is characterized by the accumulation of particular proteins in select regions of the brain. It remains unclear how dysfunction of a ubiquitous protein degradation pathway results in distinct pathologies. alpha-Synuclein is a protein whose aggregation and oligomerization has been implicated in several diseases, including Parkinson's disease (PD). Herein, we investigated regionally selective alterations in alpha-synuclein degradation to decipher potential mechanisms underlying its role in disease. Chaperone mediated autophagy (CMA), a selective route of direct lysosomal degradation, participates in the turnover of alpha-synuclein. In a mouse model of synucleinopathy, we show that the levels of the CMA receptor Lamp-2a are dynamically upregulated upon the development of motor symptoms in the regions that form the most prominent inclusions. However, increased levels of Lamp-2a were unable to induce greater lysosomal substrate binding and degradation. The regions of the brain that develop the most prominent inclusions were found to have decreased CMA activity compared to the regions of the brain that develop minimal inclusions. Additionally, markers of lysosome and autophagosome levels were decreased in the inclusion-forming regions. Therefore, multiple lysosomal deficiencies potentially contribute to the selective aggregation of alpha-synuclein. However, during such conditions of impaired degradation, many substrates are presumably affected. Therefore, we next investigated potential factors that mediate the vulnerability of alpha-synuclein to aggregation. While no defects were detected in the ability of alpha-synuclein to be recognized as a CMA substrate or unfolded for lysosomal uptake, altered levels of proteins involved in lipid metabolism were found in the regions vulnerable to inclusion formation. Finally, given the lack of correlation between Lamp-2a levels and CMA activity across brain regions, we explored the possibility that additional proteins may participate in the direct lysosomal uptake and degradation of substrates. These data provide evidence of regional insufficiencies in lysosomal function that underlie the selective initiation of alpha-synuclein aggregation.
Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: .
Adviser: Harry Ischiropoulos.
Thesis (Ph.D.)--University of Pennsylvania, 2011.
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School code: 0175.
University of Pennsylvania.
Contained In:
Dissertation Abstracts International 73-06B.
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Restricted for use by site license.
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