PgmNr D1344: Using Drosophila to uncover the molecular mechanisms underlying Pontocerebellar Hypoplasia.

Authors:
Vafa Bayat 1 ; Xue Yang 1,2 ; Zhihao Wu 1 ; Yen-Chi Wu 1 ; Hannes Vogel 1 ; Bingwei Lu 1


Institutes
1) Stanford University, Stanford, CA; 2) Peking University, Beijing, China.


Keyword: neural degeneration

Abstract:

The molecular and cellular pathology of the neonatal/fetal disease Pontocerebellar Hypoplasia (PCH) is poorly understood. PCH is a rare congenital disorder displaying autosomal recessive inheritance characterized by hypoplasia and atrophy of the cerebellar cortex, dentate nuclei, pontine nuclei and inferior olives. A growing number of mutated genes have been implicated in this disease. Several hypotheses have been proposed regarding the relationships between these recently identified genes and the potential mechanisms, but evidence is lacking. Molecular genetic analysis in model organisms such as Drosophila has the potential to make up for the deficits in our understanding of PCH pathogenesis and offer more in-depth mechanistic insights. We have obtained and are generating mutants using imprecise excision and CRISPR in all of the TSEN complex genes, which have all been found to be mutated in this disease.  Our data is supportive of a neurodegenerative process taking place in these mutants and our hypothesis that dysregulation of levels of key proteins implicated in other neurodegenerative diseases is present and are testing which of these are pathogenic using genetic interactions with RNAi lines, loss of function lines and overexpression.  Determining which pathways and proteins are involved in the pathogenesis will also give clues to potential treatments, which are presently only supportive in nature.