Caspase-2 is a member of the caspase family that exhibits both apoptotic and non-apoptotic properties, and has been shown to mediate synaptic deficits in models of several neurological conditions, including Alzheimer’s disease (AD), Huntington’s disease (HD), and Lewy Body dementia (LBD). Our lab previously reported that caspase-2 protein levels are elevated in these diseases, leading us to hypothesize that elevated caspase-2 protein levels are due to increased transcription of caspase-2 mRNA. There are two major isoforms of caspase-2 mRNA, caspase-2L and caspase-2S. We tested our hypothesis by measuring the levels of these mRNA isoforms normalized to levels of RPL13 mRNA, a reference gene that showed no disease-associated changes. Here, we report no increases in caspase-2L mRNA levels in any of the three diseases studied, AD (with mild cognitive impairment (MCI)), HD and LBD, disproving our hypothesis. Caspase-2S mRNA showed a non-significant downward trend in AD. We also analyzed expression levels of SNAP25 and βIII-tubulin mRNA. SNAP25 mRNA was significantly lower in AD and there were downward trends in MCI, LBD, and HD. βIII-tubulin mRNA expression remained unchanged between disease groups and controls. These findings indicate that factors besides transcriptional regulation cause increases in caspase-2 protein levels. The reduction of SNAP25 mRNA expression suggests that presynaptic dysfunction contributes to cognitive deficits in neurodegeneration.
Bibliographical noteFunding Information:
Sources of funding for this study include the T. and P. Grossman Family Foundation (K.H. A.), B. Grossman (K.H.A.) and K. Moe (K.H.A.), ADRC and MCSA of the Mayo Clinic (funding supported by National institutes of Health; NIA: U01 AG006786, P30AG062677, R01AG034676). funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Dr. Jean P. Vonsattel (Columbia University) for supplying HD samples and Dr. Dirk Keene (Washington University) for supplying LBD samples. We also acknowledge our collaboration Dr. David Knopman and the ADRC and MCSA of the Mayo Clinic for supplying AD/MCI samples.
© 2022 Hlynialuk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't