Gerard W. O'Keeffe

Parkinson's disease (PD) is characterised by progressive loss of dopaminergic (DA) neurons from the substantia nigra (SN) and α‐synuclein (αSyn) accumulation. Age is the biggest risk factor for PD and may create a vulnerable pre‐parkinsonian state, but the drivers of this association are unclear. It is known that ageing increases αSyn expression in DA neurons and that this may alter molecular processes that are central to maintaining nigrostriatal integrity. To model this, adult female Sprague–Dawley rats received a unilateral intranigral injection of adeno‐associated viral (AAV) vector carrying wild‐type human αSyn (AAV‐αSyn) or control vector (AAV‐Null). AAV‐αSyn induced no detrimental effects on motor behaviour, but there was expression of human wild‐type αSyn throughout the midbrain and ipsilateral striatum at 20 weeks post‐surgery. Microarray analysis revealed that the gene most‐upregulated in the ipsilateral SN of the AAV‐αSyn group was the SKI Family Transcriptional Corepressor 1 (SKOR1). Bioenergetic state analysis of mitochondrial function found that SKOR1 overexpression reduced the maximum rate of cellular respiration in SH‐SY5Y cells. Furthermore, experiments in SH‐SY5Y cells revealed that SKOR1 overexpression impaired neurite growth to the same extent as αSyn, and inhibited BMP‐SMAD‐dependent transcription, a pathway that promotes DA neuronal survival and growth. Given the normal influence of ageing on DA neuron loss in human SN, the extent of αSyn‐induced SKOR1 expression may influence whether an individual undergoes normal nigrostriatal ageing or reaches a threshold for prodromal PD. This provides new insight into mechanisms through which ageing‐related increases in αSyn may influence molecular mechanisms important for the maintenance of neuronal integrity.

Maternal immune activation (MIA) during gestation has been implicated in the development of neurological disorders such as schizophrenia and autism. Epidemiological studies have suggested that the effect of MIA may depend on the gestational timing of the immune challenge and the region of the central nervous system (CNS) in question. This study investigated the effects of MIA with 100 μg/kg lipopolysaccharide at either Embryonic days (E)12 or E16 on the oligodendrocytes, microglia and astrocytes of the offspring spinal cord. At E16, MIA decreased the number of olig2 + and Iba‐1 + cells in multiple grey and white matter regions of the developing spinal cord 5 h after injection. These decreases were not observed at postnatal day 14. In contrast, MIA at E12 did not alter Olig2 + or Iba‐1 + cell number in the developing spinal cord 5 h after injection, however, Olig2 + cell number was decreased in the ventral grey matter of the P14 spinal cord. No changes were observed in glial fibrillary acidic protein (GFAP) expression at P14 following MIA at either E12 or E16. These data suggest that E16 may be a window of immediate vulnerability to MIA during spinal cord development, however, the findings also suggest that the developmental process may be capable of compensation over time. Potential changes in P14 animals following the challenge at E12 are indicative of the complexity of the effects of MIA during the developmental process.