Cerebellar developmental deficits underlie neurodegenerative disorder spinocerebellar ataxia type 23

Abstract

Spinocerebellar ataxia type 23 (SCA23) is a late-onset neurodegenerative disorder characterized by slowly progressive gait and limb ataxia, for which there is no therapy available. It is caused by pathogenic variants in PDYN, which encodes prodynorphin (PDYN). PDYN is processed into the opioid peptides α-neoendorphin and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signaling, stress-induced responses and addiction. Variants causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYN R212W mice express human PDYN containing the SCA23 variant p.R212W. These mice show progressive motor deficits from 3 months of age, climbing fiber (CF) deficits from 3 months of age, and Purkinje cell (PC) loss from 12 months of age. A mouse model for SCA1 showed similar CF deficits, and a recent study found additional developmental abnormalities, namely increased GABAergic interneuron connectivity and non-cell autonomous disruption of PC function. As SCA23 mice show a similar pathology to SCA1 mice in adulthood, we hypothesized that SCA23 may also follow SCA1 pathology during development. Examining PDYN R212W cerebella during development, we uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma, possibly leading to the observed delay in early phase CF elimination between 2 and 3 weeks of age. Furthermore, CFs did not reach terminal height, leaving proximal PC dendrites open to be occupied by parallel fibers (PFs). The observed increase in vGlut1 protein-a marker for PF-PC synapses-indicates that PFs indeed take over CF territory and have increased connectivity with PCs. Additionally, we detected altered expression of several critical Ca 2+ channel subunits, potentially contributing to altered Ca 2+ transients in PDYN R212W cerebella. These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum. Smeets et al Smeets et al Developmental deficits in SCA23 Brain Pathology 0 (2020) 1-15

A Massively Parallel CRISPR-Based Screening Platform for Modifiers of Neuronal Activity

“…CACNG7 encodes γ-7, which is related to stargazing, has been found to be reduced in mouse models of spinocerebellar ataxia type 23 (SCA24). 50 In the screen, CACNG7 KD increased neuronal excitability and we observe a general increase in neuronal excitability in CACNG7 KD neurons in independent experiments (Figure 5b). PTEN , classically associated with its role as a tumor suppressor gene 51 and in mitophagy, 52 has been shown to modulate neurite outgrowth and synapse density in PTEN KO mice.…”

Pathological Bergmann glia alterations and disrupted calcium dynamics in ataxic Canavan disease mice

“…PF-PC synaptic dysfunction is common in several mouse models of ataxia (including the ATXN1 mouse model for spinocerebellar ataxia; Barnes et al, 2011;Ebner et al, 2013;Hoxha et al, 2016;Koeppen, 2005;Smeets et al, 2021;Zuo et al, 1997) and frequently observed in conjunction with BG dysfunction (Burright et al, 1995;Custer et al, 2006;Shiwaku et al, 2013). Disruption Quantification of the number of MAP2+ neurons present in primary neonatal murine astroglia-neuron cocultures derived from WT mice = gray and cells derived from constitutive Slc13a3 knockout mice (Slc13a3 À/À ) = green.…”

“…We show that BG irregularities predate PF–PC synaptogenesis and coincide with the final stages of CF pruning ( Crepel et al, 1976 ; Hashimoto & Kano, 2013 ), BG differentiation is temporally and functionally correlated with PC dendritic outgrowth and synaptogenesis in the molecular layer occurring around the second postnatal week ( Yamada & Watanabe, 2002 ). PF–PC synaptic dysfunction is common in several mouse models of ataxia (including the ATXN1 mouse model for spinocerebellar ataxia; Barnes et al, 2011 ; Ebner et al, 2013 ; Hoxha et al, 2016 ; Koeppen, 2005 ; Smeets et al, 2021 ; Zuo et al, 1997 ) and frequently observed in conjunction with BG dysfunction ( Burright et al, 1995 ; Custer et al, 2006 ; Shiwaku et al, 2013 ). Disruption of CF–PC synapses is seen in postmortem tissue from patients with spinocerebellar ataxias, Parkinson's disease, and essential tremor ( Koeppen, 2005 ; Kuo et al, 2017 ; Lin et al, 2014 ).…”

Endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses

“…Interestingly, CF loss has been observed to precede Purkinje cell degeneration in some cases, indicating a potential role in disease progression (Smeets et al, 2015). The loss of CFs in SCAs is frequently accompanied by the strengthening of PF synapses, a process known as heterosynaptic competition (Hashimoto and Kano, 2013; Smeets et al, 2021; Sotelo et al, 1975). Given that CFs and PFs innervate distinct regions of the dendritic arbours of Purkinje cells – with CFs populating the proximal dendritic tree and PFs synapsing on the distal dendrites - the loss of one fiber type typically leads to an increase in the other (Miyazaki et al, 2012; Miyazaki et al, 2010; Taisuke et al, 2004).…”