Mutant α-synuclein exacerbates age-related decrease of neurogenesis

In Parkinson disease, wild-type α-synuclein accumulates during aging, whereas α-synuclein mutations lead to an early onset and accelerated course of the disease. The generation of new neurons is decreased in regions of neurogenesis in adult mice overexpressing wild-type human α-synuclein. We examined the subventricular zone/olfactory bulb neurogenesis in aged mice expressing either wild-type human or A53T mutant α-synuclein. Aging wild-type and mutant α-synuclein-expressing animals generated significantly fewer new neurons than their non-transgenic littermates. This decreased neurogenesis was caused by a reduction in cell proliferation within the subventricular zone of mutant α-synuclein mice. In contrast, no difference was detected in mice overexpressing the wild-type allele. Also, more TUNEL-positive profiles were detected in the subventricular zone, following mutant α-synuclein expression and in the olfactory bulb, following wild-type and mutant α-synuclein expression. The impaired neurogenesis in the olfactory bulb of different transgenic α-synuclein mice during aging highlights the need to further explore the interplay between olfactory dysfunction and neurogenesis in Parkinson disease.