Abstract
Background
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 mutations in PDYN, which encodes the opioid precursor protein prodynorphin (PDYN). PDYN is processed into the opioid peptides α-neoendorphin, and dynorphins (Dyn) A and B; inhibitory neurotransmitters that function in pain signalling, stress-induced responses, and addiction. Mutations causing SCA23 mostly affect Dyn A, leading to loss of secondary structure and increased peptide stability. PDYNR212W mice express human PDYN containing the SCA23 p.R212W mutation. These mice show gait deficits and progressive loss of motor function from 3 months of age. The cerebella of PDYNR212W mice show climbing fibre (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 hyperproliferation of stem cells leading to 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.
Methods
In the present study, we examined the cerebella of PDYNR212W mice during cerebellar development, from 2 to 8 weeks of age, using immunohistochemistry, protein, and RNA analysis.
Results
We uncovered developmental deficits from 2 weeks of age, namely a reduced number of GABAergic synapses on PC soma in PDYNR212W mice, 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 fibres (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 Ca2+ channel subunits, potentially contributing to altered Ca2+ transients in PDYNR212W cerebella.
Conclusions
These findings indicate that developmental abnormalities contribute to the SCA23 pathology and uncover a developmental role for PDYN in the cerebellum.
Spinocerebellar ataxia type 6 in Brazil
