Intermediate and Expanded HTT Alleles and the Risk for alpha-Synucleinopathies
Por:
Perez-Oliveira, S, Alvarez, I, Rosas, I, Menendez-Gonzalez, M, Blazquez-Estrada, M, Aguilar, M, Corte, D, Buongiorno, M, Molina-Porcel, L, Aldecoa, I, Marti, MJ, Sanchez-Juan, P, Infante, J, Gonzalez-Aramburu, I, Garcia-Gonzalez, P, Rosende-Roca, M, Boada, M, Ruiz, A, Perinan, MT, Macias-Garcia, D, Munoz-Delgado, L, Gomez-Garre, P, Mir, P, Clarimon, J, Lleo, A, Alcolea, D, De la Casa-Fages, B, Duarte, I, Alvarez, V, Pastor, P
Publicada:
1 sep 2022
Ahead of Print:
1 jul 2022
Resumen:
Background: Previous studies suggest a link between CAG repeat number in the HTT gene and non-Huntington neurodegenerative diseases.
Objective: The aim is to analyze whether expanded HTT CAG alleles and/or their size are associated with the risk for developing alpha-synucleinopathies or their behavior as modulators of the phenotype.
Methods: We genotyped the HTT gene CAG repeat number and APOE-sigma isoforms in a case-control series including patients with either clinical or neuropathological diagnosis of alpha-synucleinopathy.
Results: We identified three Parkinson's disease (PD) patients (0.30%) and two healthy controls (0.19%) carrying low-penetrance HTT repeat expansions whereas none of the dementia with Lewy bodies (DLB) or multisystem atrophy (MSA) patients carried pathogenic HTT expansions. In addition, a clear increase in the number of HTT CAG repeats was found among DLB and PD groups influenced by the male gender and also by the APOE4 allele among DLB patients. HTT intermediate alleles' (IAs) distribution frequency increased in the MSA group compared with controls (8.8% vs. 3.9%, respectively). These differences were indeed statistically significant in the MSA group with neuropathological confirmation. Two MSA HTT CAG IAs carriers with 32 HTT CAG repeats showed isolated polyQ inclusions in pons and basal nuclei, which are two critical structures in the neurodegeneration of MSA.
Conclusions: Our results point to a link between HTT CAG number, HTT IAs, and expanded HTT CAG repeats with other non-HD brain pathology and support the hypothesis that they can share common neurodegenerative pathways. (c) 2022 International Parkinson and Movement Disorder Society.
Filiaciones:
Perez-Oliveira, S:
Hosp Univ Cent Asturias, Lab Genet, Oviedo 33011, Asturias, Spain
Alvarez, I:
Univ Hosp Mutua Terrassa, Dept Neurol, Movement Disorders Unit, Barcelona, Spain
Fdn Docencia & Recerca Mutua Terrassa, Barcelona, Spain
Rosas, I:
Hosp Univ Cent Asturias, Lab Genet, Oviedo 33011, Asturias, Spain
Menendez-Gonzalez, M:
Hosp Univ Cent Asturias, Dept Neurol, Oviedo, Spain
Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Blazquez-Estrada, M:
Hosp Univ Cent Asturias, Dept Neurol, Oviedo, Spain
Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Aguilar, M:
Univ Hosp Mutua Terrassa, Dept Neurol, Movement Disorders Unit, Barcelona, Spain
Fdn Docencia & Recerca Mutua Terrassa, Barcelona, Spain
Corte, D:
Hosp Univ Cent Asturias HUCA, Biobank Principado Asturias, Oviedo, Spain
Buongiorno, M:
Univ Hosp Mutua Terrassa, Dept Neurol, Movement Disorders Unit, Barcelona, Spain
Fdn Docencia & Recerca Mutua Terrassa, Barcelona, Spain
Molina-Porcel, L:
Hosp Clin Barcelona, Neurol Dept, Alzheimers Dis & Other Cognit Disorders Unit, Barcelona, Spain
Inst Invest Biomed August Pi i Sunyer, Barcelona, Spain
Biobank Hosp Clin IDIBAPS, Neurol Tissue Bank, Barcelona, Spain
Aldecoa, I:
Biobank Hosp Clin IDIBAPS, Neurol Tissue Bank, Barcelona, Spain
Univ Barcelona, Hosp Clin Barcelona, Biomed Diagnost Ctr, Pathol Dept, Barcelona, Spain
Marti, MJ:
Hosp Clin Barcelona, Dept Neurol, Parkinsons Dis & Movement Disorders Unit, Barcelona, Spain
Univ Barcelona, Maeztu Ctr, Inst Neurociencies, Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona, Spain
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Sanchez-Juan, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
ISCIII, CIEN Fdn, Alzheimers Ctr Reina Sofia, Madrid, Spain
Infante, J:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Cantabria, Marques Valdecilla Univ Hosp, Dept Neurol, Santander, Spain
IDIVAL, Santander, Spain
Gonzalez-Aramburu, I:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Cantabria, Marques Valdecilla Univ Hosp, Dept Neurol, Santander, Spain
IDIVAL, Santander, Spain
Garcia-Gonzalez, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr, Barcelona, Spain
Univ Int Catalunya, Fdn ACE, Memory Clin, Barcelona, Spain
Rosende-Roca, M:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr, Barcelona, Spain
Univ Int Catalunya, Fdn ACE, Memory Clin, Barcelona, Spain
Boada, M:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr, Barcelona, Spain
Univ Int Catalunya, Fdn ACE, Memory Clin, Barcelona, Spain
Ruiz, A:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Int Catalunya, Inst Catala Neurociencies Aplicades, Res Ctr, Barcelona, Spain
Univ Int Catalunya, Fdn ACE, Memory Clin, Barcelona, Spain
Perinan, MT:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla, CSIC,Dept Neurol & Neurophysiol,Movement Disorder, Seville, Spain
Macias-Garcia, D:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla, CSIC,Dept Neurol & Neurophysiol,Movement Disorder, Seville, Spain
Munoz-Delgado, L:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla, CSIC,Dept Neurol & Neurophysiol,Movement Disorder, Seville, Spain
Gomez-Garre, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla, CSIC,Dept Neurol & Neurophysiol,Movement Disorder, Seville, Spain
Mir, P:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Seville, Hosp Univ Virgen Rocio, Inst Biomed Sevilla, CSIC,Dept Neurol & Neurophysiol,Movement Disorder, Seville, Spain
Univ Seville, Fac Med, Dept Med, Seville, Spain
Clarimon, J:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Dept Neurol, Barcelona, Spain
Lleo, A:
Natl Inst Hlth Carlos III, Network Ctr Biomed Res Neurodegenerat Dis, CIBERNED, Madrid, Spain
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Dept Neurol, Barcelona, Spain
Alcolea, D:
Univ Autonoma Barcelona, Hosp Santa Creu & St Pau, IIB St Pau, Dept Neurol, Barcelona, Spain
De la Casa-Fages, B:
Hosp Gen Univ Gregorio Maranon, Dept Neurol, Movement Disorders Unit, Madrid, Spain
Inst Invest Sanitaria Gregorio Marano, Madrid, Spain
Duarte, I:
Hosp Univ Cent Asturias, Lab Genet, Oviedo 33011, Asturias, Spain
Alvarez, V:
Hosp Univ Cent Asturias, Lab Genet, Oviedo 33011, Asturias, Spain
Inst Invest Sanitaria Principado Asturias ISPA, Oviedo, Spain
Pastor, P:
Univ Hosp Germans Trias & Pujol, Dept Neurol, Unit Neurodegenerat Dis, Barcelona, Spain
Germans Trias & Pujol Res Inst IGTP Badalona, Barcelona, Spain
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