Reduced brain‐derived neurotrophic factor (BDNF) mRNA expression and presence of BDNF‐immunoreactive granules in the spinocerebellar ataxia type 6 (SCA6) cerebellum

Abstract

Spinocerebellar ataxia type 6 (SCA6) is an autosomal-dominant neurodegenerative disorder caused by a small expansion of tri-nucleotide (CAG) repeat encoding polyglutamine (polyQ) in the gene for α(1A) voltage-dependent calcium channel (Ca(v) 2.1). Thus, this disease is one of the nine neurodegenerative disorders called polyQ diseases. The Purkinje cell predominant neuronal loss is the characteristic neuropathology of SCA6, and a 75-kDa carboxy-terminal fragment (CTF) of Ca(v) 2.1 containing polyQ, which remains soluble in normal brains, becomes insoluble in the cytoplasm of SCA6 Purkinje cells. Because the suppression of the brain-derived neurotrophic factor (BDNF) expression is a potentially momentous phenomenon in many other polyQ diseases, we implemented BDNF expression analysis in SCA6 human cerebellum using quantitative RT-PCR for the BDNF mRNA, and by immunohistochemistry for the BDNF protein. We observed significantly reduced BDNF mRNA levels in SCA6 cerebellum (n = 3) compared to controls (n = 6) (Mann-Whitney U-test, P = 0.0201). On immunohistochemistry, BDNF protein was only weakly stained in control cerebellum. On the other hand, we found numerous BDNF-immunoreactive granules in dendrites of SCA6 Purkinje cells. We did not observe similar BDNF-immunoreactive granules in other polyQ diseases, such as Huntington's disease or SCA2. As we often observed that the 1C2-positive Ca(v) 2.1 aggregates existed more proximally than the BDNF-positive granules in the dendrites, we speculated that the BDNF protein trafficking in dendrites may be disturbed by Ca(v) 2.1 aggregates in SCA6 Purkinje cells. We conclude that the SCA6 pathogenic mechanism associates with the BDNF mRNA expression reduction and abnormal localization of BDNF protein.

Cerebellar Development and Circuit Maturation: A Common Framework for Spinocerebellar Ataxias

“…Similar results were obtained when the expression of TrkB was specifically downregulated in CFs (Choo et al, 2017). Accordingly, qRT-PCR analysis of post-mortem cerebellar samples from SCA6 patients revealed a significant decrease in the expression of BDNF transcripts (Takahashi et al, 2012), and an impairment in synaptic elimination of weaker CFs in the Ca v 2.1[84Q] SCA6 mouse model (Jayabal et al, 2017).…”

Withdrawal of BDNF from hippocampal cultures leads to changes in genes involved in synaptic function

“…A lack of BDNF will likely affect pre-and postsynaptic functions and may lead to morphological changes and synaptic failure. In fact, many studies have documented a decrease in BDNF levels in neurodegenerative diseases, most notably in AD (Narisawa-Saito et al, 1996;Connor et al, 1997;Nagahara et al, 2009), HD (Zuccato et al, 2008) and Spinocerebellar ataxia (Takahashi et al, 2012). Administration of BDNF has been shown to be neuroprotective against age-related hippocampal synaptic loss (Nagahara et al, 2009(Nagahara et al, , 2013.…”

Cytoplasmic Location of α1A Voltage-Gated Calcium Channel C-Terminal Fragment (Cav2.1-CTF) Aggregate Is Sufficient to Cause Cell Death

“…Furthermore, co-localization of CREB and cytoplasmic Ca v 2.1 aggregates was confirmed in human SCA6 Purkinje cells, suggesting that the suppression of CREB-mediated transcription takes place in SCA6 Purkinje cells. Indeed, we recently found that the brain derived neurotrophic factor (BDNF) mRNA, which is regulated by the CREB-mediated transcription, is reduced in SCA6 human cerebellum [26]. It is also important to note that the CREB and p-CREB were not reduced even when the rCTF was over-expressed in the nuclei by tagging the rCTF with NLS.…”