Mutant α-synuclein exacerbates age-related decrease of neurogenesis

Abstract

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.

Introduction

In Parkinson disease (PD), as well as in other synucleinopathies, the accumulation of misfolded α-synuclein within neuronal cell bodies, axons and synapses has been proposed to be one of the crucial pathogenic hallmarks (Hashimoto and Masliah, 1999, Takeda et al., 1998). α-Synuclein is a 140-amino acid synaptic molecule that was originally identified as the non-Aβ component precursor protein of Alzheimer disease amyloid plaques (Iwai et al., 1996). A physiological role of α-synuclein has been proposed in developmental plasticity and synaptic remodeling (Chandra et al., 2004, George et al., 1995, Hsu et al., 1998). Point mutations in α-synuclein (A53T, A30P, E46K) have been identified in rare Mendelian forms of familial PD designated as PARK1 (Kruger et al., 1998, Polymeropoulos et al., 1997, Zarranz et al., 2004).

These α-synuclein mutations accelerate its aggregation and oligomerization (Conway et al., 1998, Narhi et al., 1999). As a result, in patients affected by the α-synuclein A53T mutation, the age of onset is much earlier than for patients presenting with sporadic PD (Kruger et al., 1998, Polymeropoulos et al., 1997, Zarranz et al., 2004). In PD, accumulation of α-synuclein aggregates has not only been observed in the midbrain and brain stem nuclei, but also in the olfactory bulb at a very early stage of the disease (Braak et al., 2003). Accumulation of α-synuclein in the olfactory bulb is particularly of clinical relevance, because olfactory dysfunction is one of the early symptoms in PD (Berendse et al., 2001, Sobel et al., 2001). Moreover, other neurodegenerative diseases such as Alzheimer disease or dementia with Lewy bodies result in olfactory dysfunction too (for review see Hawkes, 2006). The pathology in the olfactory bulb correlates strongly with the disease progression in dementia (Jellinger and Attems, 2005, Ohm and Braak, 1987, Tsuboi et al., 2003).

The olfactory bulb is one of the regions, where new neurons are constantly added to the olfactory circuitry throughout lifetime. The proliferating neural stem cells (NSCs) residing in the basal forebrain subventricular zone (SVZ) give constantly rise to neuronal precursors and therefore constitute the keystone of the olfactory bulb neurogenesis (Reynolds and Weiss, 1992). Newly generated neuronal precursors leave the SVZ and migrate along the rostral migratory stream (RMS) towards the olfactory bulb (Lois and Alvarez-Buylla, 1994). Upon arrival, newly generated cells mature and integrate as interneurons into the granule cell and the glomerular layer of the olfactory bulb (Betarbet et al., 1996, Winner et al., 2002). Furthermore, our previous work showed that continuous overproduction and turnover of newly generated neurons is an important regulatory feature of the adult olfactory bulb neurogenesis (Winner et al., 2002). The functional integration of the newly generated interneurons into the olfactory neuronal circuitry (Carlen et al., 2002, Carleton et al., 2003) strongly suggests a relevance of adult neurogenesis in olfaction (Magavi et al., 2005).

To further elucidate the α-synuclein-associated pathological mechanisms, animal models for synucleinopathies have been established using various promoters to drive expression of α-synuclein. The neuropathological changes observed in these models included protein accumulation in different areas of the brain according to a promoter-dependent topography (Masliah et al., 2000, Rockenstein et al., 2002). For example, PDGF-promoter driven expression of mutant A53T α-synuclein has resulted in a transgenic mouse model with a severe motor impairment (Hashimoto et al., 2003). α-Synuclein is endogenously expressed in NSCs and their progeny in the adult SVZ/olfactory bulb system as well as in the hippocampus (Li et al., 2002, Winner et al., 2004). Recently, using a transgenic mouse line that expresses high levels of wild-type human α-synuclein (WTS) we reported that increased levels of WTS affected adult neurogenesis. In particular, increased α-synuclein, obtained via transgenic expression of human α-synuclein led to the death of immature neurons in the brain of adult animals, indicating that α-synuclein has an impact on adult neurogenesis (Winner et al., 2004).

Clinical manifestations of synucleinopathies occur to a large extent in advanced age. We therefore examined the impact of α-synuclein on olfactory bulb neurogenesis during aging using the models of (i) transgenic mice overexpressing WTS and (ii) transgenic mice expressing the mutant A53T α-synuclein (MTS), a mutation accelerating the α-synuclein aggregation.