Recent studies have reported that alleles in the premutation range in the
FMR1 gene in males result in increased FMR1 mRNA levels and at the same
time mildly reduced FMR1 protein levels. Some elderly males with
premutations exhibit an unique neurodegenerative syndrome characterized by
progressive intention tremor and ataxia. We describe neurohistological,
biochemical and molecular studies of the brains of mice with an expanded
CGG repeat and report elevated Fmr1 mRNA levels and intranuclear
inclusions with ubiquitin, Hsp40 and the 20S catalytic core complex of the
proteasome as constituents. An increase was observed of both the number
and the size of the inclusions during the course of life, which correlates
with the progressive character of the cerebellar tremor/ataxia syndrome in
humans. The observations in expanded-repeat mice support a direct role of
the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the
formation of the inclusions and suggest a correlation between the presence
of intranuclear inclusions in distinct regions of the brain and the
clinical features in symptomatic premutation carriers. This mouse model
will facilitate the possibilities to perform studies at the molecular
level from onset of symptoms until the final stage of the disease