| Ph.D.: |
Hebrew
University of Jerusalem, 1976 |
| Phone: |
(Office):
+972-3-6408984
(Lab): +972-3-6406695
(Home): +972-3-6094174
Fax (Office): +972-3-6406834
|
| E-mail: |
shoshbn@tauex.tau.ac.il
|
| Room#: |
Room
613 (office); room 611 (lab) |
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Yeast as a model
system to for neurodegenerative disorders
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Quality control
mechanisms function in the frontline of cellular
response to aberrant proteins. A major problem
inherent to aberrant proteins is their tendency to
form aggregates that are toxic to cells, and many human diseases are
caused by such aggregations. For example, the
incurable Huntington's disease (HD)
is a progressive neurodegenerative disorder
caused by genetic mutations that generate extended
polyglutamine (polyQ) tracts in huntingtin,
leading to its aggregation and eventual death of
neurons. Aggregation
diseases are multi-factorial and caused by
disturbed homeostasis between aggregation-prone
proteins load and cellular capacity to handle
them. Molecular chaperones are key cellular
components that handle such
proteins and indeed, the molecular chaperone
p97 and its yeast homologue Cdc48 were identified
as polyQ-interacting proteins and human p97 was
implicated in inclusion body myopathy
associated with Paget disease of bone and
frontotemporal dementia.
Age is a key factor in every aggregation
disease. The
age of
HD
onset is
inversely correlated with the
number of Q repeats, and even a mid-size polyQ
tract may lead to HD at a later age. We
hypothesize that polyQ aggregation is
aggravated by a combination of aging and at
least one additional insult such as dwindling
of or accumulation of incapacitating mutations
in key cellular components, as well as growth
conditions that affect cellular metabolism.
Since aging and protein aggregation are
multi-factorial complex processes, we exploit
the excellent
genetic tools afforded by
Saccharomyces cerevisiae
and comprehensive experimental
approaches for a
combinatorial study of polyQ aggregation and
aging.
Aggregation can be easily monitored by fluorescent microscopy or a simple filtration assay. The involvement of Cdc48 in polyQ aggregation is addressed by screening for known and novel cofactors, substitutes and regulators of Cdc48 that ameliorate aggregation of the toxic long polyQ (103Q) huntingtin fragment. The non-toxic mid-size polyQ (47Q) huntingtin fragment is used as a sensitive biosensor for the identification of age-related pro- or anti-aggregation genes and conditions and for the discovery of anti-aggregation drugs.
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