DRPLA: recent advances in research using transgenic mouse models.

Dentatorubral-pallidoluysian atrophy (DRPLA) is one form of trinucleotide repeat disease, which has a high prevalence rate in the Japanese population. Our group established DRPLA transgenic mice harboring a single copy of a full-length human mutant DRPLA gene with 76 CAG repeats (Q76 mice). Q76 mice showed no obvious neurological phenotype but showed somatic and intergenerational instabilities of CAG repeats which closely resembled those in human DRPLA. During the breeding of Q76 mice, we serendipitously generated an additional strain with 129 repeats by "en masse" expansion of CAG repeats (Q129 mice). These two substrains are ideal models for the investigation of CAG-repeat-dependent pathogenesis of DRPLA, because they have the same genetic background except for the length of CAG repeats. Q129 mice showed a marked neurological phenotype and massive neuronal intranuclear accumulation (NIA) of mutant proteins, but showed no obvious neuronal loss. Through detailed investigations of these two substrains, we believe that "neuronal dysfunction without neuronal loss" is the key concept in the pathogenesis of DRPLA.