Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to stimulation: male microglia tended to have a more pro-inflammatory phenotype, while female microglia showed increased sensitivity to conduritol-B-epoxide (CBE), a small molecule inhibitor of glucocerebrosidase, the enzyme encoded by the GBA1 gene, mutations of which are the major risk factor for Parkinson’s Disease (PD). Interestingly, glucocerebrosidase inhibition particularly impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons, attenuating the sex differences observed in this neuroprotective function. This finding is consistent with the clinical impact of GBA1 mutations, in which the 1.5–2-fold reduced risk of developing idiopathic PD observed in female individuals is lost in the GBA1 carrier population, thus suggesting a sex-specific role for microglia in the etiopathogenesis of PD-GBA1.

Sex-specific microglial responses to glucocerebrosidase inhibition: relevance to GBA1-linked Parkinson disease / E.A.S. Brunialti, A.M.G. Villa, M. Toffoli, S. Lucas Del Pozo, N. Rizzi, C. Meda, A.C. Maggi, A.H.V. Schapira, P. Ciana. - In: CELLS. - ISSN 2073-4409. - 12:3(2023 Feb), pp. 343.1-343.20. [10.3390/cells12030343]

Sex-specific microglial responses to glucocerebrosidase inhibition: relevance to GBA1-linked Parkinson disease

E. Brunialti
Primo
;
A. Villa
Secondo
;
N. Rizzi;C. Meda;A. Maggi;P. Ciana
Ultimo
2023

Abstract

Microglia are heterogenous cells characterized by distinct populations each contributing to specific biological processes in the nervous system, including neuroprotection. To elucidate the impact of sex-specific microglia heterogenicity to the susceptibility of neuronal stress, we video-recorded with time-lapse microscopy the changes in shape and motility occurring in primary cells derived from mice of both sexes in response to pro-inflammatory or neurotoxic stimulations. With this morpho-functional analysis, we documented distinct microglia subpopulations eliciting sex-specific responses to stimulation: male microglia tended to have a more pro-inflammatory phenotype, while female microglia showed increased sensitivity to conduritol-B-epoxide (CBE), a small molecule inhibitor of glucocerebrosidase, the enzyme encoded by the GBA1 gene, mutations of which are the major risk factor for Parkinson’s Disease (PD). Interestingly, glucocerebrosidase inhibition particularly impaired the ability of female microglia to enhance the Nrf2-dependent detoxification pathway in neurons, attenuating the sex differences observed in this neuroprotective function. This finding is consistent with the clinical impact of GBA1 mutations, in which the 1.5–2-fold reduced risk of developing idiopathic PD observed in female individuals is lost in the GBA1 carrier population, thus suggesting a sex-specific role for microglia in the etiopathogenesis of PD-GBA1.
glucocerebrosidase (GCase); microglia; Parkinson’s Disease (PD); sex-difference; shape descriptors
Settore BIO/14 - Farmacologia
feb-2023
17-gen-2023
Article (author)
File in questo prodotto:
File Dimensione Formato  
cells-12-00343-v2.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 2.83 MB
Formato Adobe PDF
2.83 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/971337
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 4
  • ???jsp.display-item.citation.isi??? 2
social impact