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Altered regulation of the PINK1 locus: a link between type 2 diabetes and neurodegeneration?

Camilla Scheele^*,1, Anders Rinnov Nielsen^,, Tomas B. Walden^,, Dean A. Sewell, Christian P. Fischer, Robert J. Brogan^*, Natasa Petrovic^*,, Ola Larsson^*, Per A. Tesch^||, Kristian Wennmalm^*, Dana S. Hutchinson^,¶, Barbara Cannon^,, Claes Wahlestedt^*,#, Bente K. Pedersen and James A. Timmons^*,,,1

^* Center for Genomics and Bioinformatics, Karolinska Institutet, Stockholm, Sweden;

Centre of Inflammation and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;

The Wenner-Gren Institute, The Arrhenius Laboratories, Stockholm University, Stockholm, Sweden;

School of Life Sciences, Heriot-Watt University, Edinburgh, Scotland, UK;

^|| Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden;

^¶ Department of Pharmacology, Monash University, Clayton, Victoria, Australia; and

^# Department of Biochemistry, The Scripps Research Institute, Jupiter, Florida, USA

¹Correspondence: C.S., Center for Genomics and Bioinformatics, Karolinska Institutet, 171 77 Stockholm, Sweden. E-mail: camilla.scheele{at}gmail.com; J.A.T., School of Life Sciences, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, U.K.. E-mail: j.timmons{at}hw.ac.uk

Mutations in PINK1 cause the mitochondrial-related neurodegenerative disease Parkinson’s. Here we investigate whether obesity, type 2 diabetes, or inactivity alters transcription from the PINK1 locus. We utilized a cDNA-array and quantitative real-time PCR for gene expression analysis of muscle from healthy volunteers following physical inactivity, and muscle and adipose tissue from nonobese or obese subjects with normal glucose tolerance or type 2 diabetes. Functional studies of PINK1 were performed utilizing RNA interference in cell culture models. Following inactivity, the PINK1 locus had an opposing regulation pattern (PINK1 was down-regulated while natural antisense PINK1 was up-regulated). In type 2 diabetes skeletal muscle, all transcripts from the PINK1 locus were suppressed and gene expression correlated with diabetes status. RNA interference of PINK1 in human neuronal cell lines impaired basal glucose uptake. In adipose tissue, mitochondrial gene expression correlated with PINK1 expression although remained unaltered following siRNA knockdown of Pink1 in primary cultures of brown preadipocytes. In conclusion, regulation of the PINK1 locus, previously linked to neurodegenerative disease, is altered in obesity, type 2 diabetes and inactivity, while the combination of RNAi experiments and clinical data suggests a role for PINK1 in cell energetics rather than in mitochondrial biogenesis.—Scheele, C., Nielsen, A. R., Walden, T. B., Sewell, D. A., Fischer, C. P., Brogan, R. J., Petrovic, N., Larsson, O., Tesch, P. A., Wennmalm, K., Hutchinson, D. S., Cannon, B., Wahlestedt, C., Pedersen, B. K., Timmons, J. A. Altered regulation of the PINK1 locus: a link between Type 2 diabetes and neurodegeneration?

Key Words: metabolism • inactivity • mitochondria • altered gene regulation