APE1 and Somatic Expansion in Huntington's Disease

ABSTRACT
Huntington’s disease (HD) is a devastating neurological disease to which no pharmacological interventions are
yet available to cure the disease. HD is caused by a mutation in the huntingtin (HTT) gene consisting of an
expanded CAG repeat. The age at which HD patients develop symptoms is considerably variable and although
the length of the pathogenic CAG repeat correlates with age of onset, individuals with equal repeat length
develop symptoms various decades after the average age of onset. This observation suggests that there are
other factors beyond the CAG repeat length that can modify the development of HD symptoms, providing
additional alternatives for the development of interventions to delay disease onset. Interestingly, genes involved
in DNA repair have been identified as potential genetic modifiers that influence age of onset. One such candidate
is APE1, the major mammalian apurinic/apyrimidinic endonuclease associated with the repair of mitochondrial
DNA (mtDNA) damage, which we have shown to be a precipitating event leading to mt dysfunction, loss of motor
function and neurodegeneration in HD. The expanded CAG repeat is somatically unstable and occurs during the
process of repairing oxidative DNA damage. We and others have elucidated important details for APE1 and
mutant HTT (mHTT) that localize to mt and reduces mt function in HD, yet our knowledge of how APE1 may
contribute to the late onset in HD patients, remains incomplete. We propose that, by preventing mtDNA damage
and somatic expansion, APE1 may be a genetic modifier that contributes to slowing HD age of onset. To test
our hypothesis, we will study if APE1 repair activity is implicated in somatic expansion and age of onset by
contributing to oxidative DNA damage and mitochondrial dysfunction. The proposed research is particularly
relevant to human health, as it will deliver an unprecedented view of APE1 and mutant HTT mechanistic functions
underlying HD age of onset and add the regulation of APE1 as a mechanism for future drug discovery in HD.

Grant Number: 5SC1NS127764-04
NIH Institute/Center: NIH
Principal Investigator: Sylvette Ayala-Pena