Brain Derived Neurotrophic Factor (BDNF) Delays Onset of Pathogenesis in Transgenic Mouse Model of Spinocerebellar Ataxia Type 1 (SCA1)

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin-1 (ATXN1) gene and characterized by motor deficits and cerebellar neurodegeneration. Even though mutant ATXN1 is expressed from an early age, disease onset usually occurs in patient’s mid-thirties, indicating the presence of compensatory factors that limit the toxic effects of mutant ATXN1 early in disease. Brain derived neurotrophic factor (BDNF) is a growth factor known to be important for the survival and function of cerebellar neurons. Using gene expression analysis, we observed altered BDNF expression in the cerebella of Purkinje neuron specific transgenic mouse model of SCA1, ATXN1[82Q] mice, with increased expression during the early stage and decreased expression in the late stage of disease. We therefore investigated the potentially protective role of BDNF in early stage SCA1 through intraventricular delivery of BDNF via ALZET osmotic pumps. Extrinsic BDNF delivery delayed onset of motor deficits and Purkinje neuron pathology in ATXN1[82Q] mice supporting its use as a novel therapeutic for SCA1.

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

“…Although it has been demonstrated that BDNF play a role in cerebellar neuropathology in SCA1 40 , the hippocampal BDNF deficiency that we determined has not been described in any other SCA animal model to date. Since BDNF plays an important role in neurite growth, neuronal survival and neurogenesis [41][42][43] , we speculate that BDNF deficiency may partially contribute to the hippocampal neuropathology described above and may represent a hopeful target for hippocampal-focused SCA1 therapy.…”

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

“…These results are suggestive of the first neuroprotective role played by astrocytes in SCA1 pathogenesis, which becomes harmful later on. Very recently, an early increase in the expression of brain-derived neurotrophic factor (BDNF) was identified as a key mediator of the initial neuroprotective role of astrocytes: an early delivery of this factor is indeed capable of delaying motor impairments and PCs pathology in a SCA1 mouse model [77]. Whether a biphasic role of astrogliosis in the disease onset also holds true for other kinds of ataxia is still needs to be elucidated.…”

“…Importantly, although a bi-phasic role of astrogliosis in ataxia pathophysiology has been so far suggested only for SCA1, these treatments may need to consider the stage of disease progression to achieve therapeutic efficacy. In a first phase of the disease, when astrocytes' reactivity may be protective [76], the inhibition of astroglial NF-κB signaling, likely effective at later stages [58], may indeed result detrimental, while BDNF delivery may delay disease onset fostering astrocytes' defensive role against neurotoxicity, at least in SCA1 [77]. Similarly, even stimulating BG/astrocytes proliferation at this stage could be a viable therapeutic intervention [118].…”

Going Too Far Is the Same as Falling Short†: Kinesin-3 Family Members in Hereditary Spastic Paraplegia

“…Complicated SPG-30 may include cerebellar dysfunction typically characterized by ataxias as cerebellar neurons would be affected similarly to other cell types by the lack of BDNF (Carter et al, 2002). In fact, Mellesmoen et al (2019) recently demonstrated that endogenously applied BDNF can delay cerebellar dysfunction onset in mouse models of ataxia. Cognitive deficits arising in complicated HSPs may be explained by similar mechanisms.…”