Differential sirtuin expression patterns in amyotrophic lateral sclerosis (ALS) postmortem tissue: neuroprotective or neurotoxic properties of sirtuins in ALS?
OBJECTIVE
Sirtuins (SIRT1-7; class III histone deactylases) modulate fundamental mechanisms in age-related neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). We assessed the expression levels of sirtuins in human postmortem ALS and control brain and spinal cord.


RESULTS
By quantitative real-time PCR, a significant reduction of SIRT1 and SIRT2 was detected in homogenates of the primary motor cortex (white and gray matter), while there were no differences in spinal cord homogenates. When specifically analyzing mRNA and protein expression in the gray matter (cortical layers I-VI of the precentral gyrus, ventral/dorsal horn of the spinal cord) by in situ hybridization histochemistry and immunohistochemistry, we found increased levels of SIRT1, SIRT2 and SIRT5 in ALS which were significant for SIRT1 and SIRT5 mRNA in the spinal cord.


CONCLUSIONS
Our results indicate a general reduction of SIRT1 and SIRT2 in ALS primary motor cortex, while in situ hybridization histochemistry and immunohistochemistry showed neuron-specific upregulation of SIRT1, SIRT2 and SIRT5, particularly in the spinal cord. Opposed effects have been described for SIRT1 and SIRT2: while SIRT1 activation is mainly associated with neuroprotection, SIRT2 upregulation is toxic to neuronal cells. Novel therapeutic approaches in ALS could therefore target SIRT1 activation or SIRT2 inhibition.
Department of Neurology, Hannover Medical School, Hannover, Germany.
Sonja
S
Körner
Sebastian
S
Böselt
Nadine
N
Thau
Klaus Jan
KJ
Rath
Reinhard
R
Dengler
Susanne
S
Petri
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use* / Q000633:toxicity*; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics*; D056565:Sirtuin 2 / Q000096:biosynthesis / Q000235:genetics* / Q000633:toxicity; D037761:Sirtuins / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity; D013116:Spinal Cord / Q000201:enzymology / Q000473:pathology
D018696:Neuroprotective Agents; C447939:SIRT1 protein, human; C474199:SIRT2 protein, human; D056564:Sirtuin 1; D056565:Sirtuin 2; D037761:Sirtuins