BAG1 is a Protective Factor for Sporadic Frontotemporal Lobar Degeneration but not for Alzheimer's Disease

Article type: Research Article

Authors: Venturelli, Eliana^{a; 1} | Villa, Chiara^{a; 1} | Fenoglio, Chiara^a | Clerici, Francesca^b | Marcone, Alessandra^c | Benussi, Luisa^d | Ghidoni, Roberta^{d; e} | Gallone, Salvatore^f | Cortini, Francesca^a | Serpente, Maria^a | Cantoni, Claudia^a | Fumagalli, Giorgio^a | Ridolfi, Elisa^a | Cappa, Stefano^{c; g} | Binetti, Giuliano^d | Franceschi, Massimo^h | Rainero, Innocenzo^f | Giordana, Maria Teresa^f | Mariani, Claudio^b | Bresolin, Nereo^a | Scarpini, Elio^a | Galimberti, Daniela^{a; *}

Affiliations: [a] Department of Neurological Sciences, “Dino Ferrari” Center, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy | [b] Center for Research and Treatment on Cognitive Dysfunctions, Chair of Neurology, University of Milan, “Luigi Sacco” Hospital, Milan, Italy | [c] Division of Neurology, San Raffaele Turro Hospital, San Raffaele Scientific Institute, Milan, Italy | [d] NeuroBioGen-Lab-Memory Clinic, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy | [e] Proteomics Unit, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy | [f] Department of Neuroscience, University of Turin, Turin, Italy | [g] Vita-Salute San Raffaele University, Milan, Italy | [h] Clinica Neurologica, Casa di Cura Santa Maria di Castellanza (Varese), Varese, Italy

Correspondence: [*] Correspondence to: Daniela Galimberti. Tel.: +39 2 55033847; Fax: +39 2 50320430; E-mail: daniela.galimberti@unimi.it.

Note: [1] These authors contributed equally to this manuscript.

Abstract: BCL2-associated athanogene 1 (BAG1) is an anti-apoptotic factor that interacts with tau and regulates its proteasomal degradation. A significant increase of the BAG-1M isoform was found in Alzheimer's disease (AD) brains, and the protein co-localized with tau and amyloid. We carried out an association study of BAG1 in a population of 291 patients clinically diagnosed with frontotemporal lobar degeneration (FTLD), none of whom was a carrier of mutations in progranulin or microtubule associated protein tau genes and 374 with AD as compared with 314 age- and gender-matched controls. In addition, another candidate named Chromatin-modifying protein 5 (CHMP5) and located in the same linkage disequilibrium block, has been included in this study. The distribution of the two single nucleotide polymorphism (SNPs), rs844239 in CHMP5 and rs706118 in BAG1, covering 100% gene variability, were determined. A statistically significant decreased allelic frequency of the BAG-1 rs706118 SNP was observed in patients with FTLD as compared with controls (16.7 versus 23.9%; p = 0.007, OR: 0.35, CI: 0.25–0.50), whereas allelic frequency of the SNP in patients with AD was similar to controls (24.3%, p > 0.05). Conversely, no significant association was found as regards CHMP5 rs844239. Stratifying according to gender, no differences were observed. BAG-1 rs706118 SNP likely acts as protective factor for sporadic FTLD, but not for AD, suggesting its specific role in a pathogenic event in FTLD. Nevertheless, a replication study would be needed to confirm these preliminary results.

Keywords: Alzheimer's disease, BAG1, CHMP5, frontotemporal lobar degeneration, neurodegeneration, polymorphism, risk factor

DOI: 10.3233/JAD-2010-101416

Journal: Journal of Alzheimer's Disease, vol. 23, no. 4, pp. 701-707, 2011