Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

PIAS2-mediated blockade of IFN-beta signaling: a basis for sporadic Parkinson disease dementia: a basis for sporadic Parkinson disease dementia

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Whole-exome sequencing identifies genes associated with Tourette's disorder in multiplex families

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. The familial and genetic contribution to the association between depression and cardiovascular disease: a twin cohort study

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Hippocampal neurons respond to brain activity with functional hypoxia

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. A major role for common genetic variation in anxiety disorders

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. DNAJB6b is Downregulated in Synucleinopathies

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Cerebrospinal fluid and plasma distribution of anti-α-synuclein IgMs and IgGs in multiple system atrophy and Parkinson's disease

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Quantitative Cellular Changes in the Thalamus of Patients with Multiple System Atrophy

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. TDP-43-specific Autoantibody Decline in Patients With Amyotrophic Lateral Sclerosis

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Joana Magalhaes
  • Emilie Tresse
  • Patrick Ejlerskov
  • Erling Hu
  • Yawei Liu
  • Andrea Marin
  • Alexia Montalant
  • Letizia Satriano
  • Carsten Friis Rundsten
  • Eva Maria Meier Carlsen
  • Rasmus Rydbirk
  • Ali Sharifi-Zarchi
  • Jesper Bøje Andersen
  • Susana Aznar
  • Tomasz Brudek
  • Konstantin Khodosevich
  • Marco Prinz
  • Jean-François Marie Perrier
  • Manu Sharma
  • Thomas Gasser
  • Shohreh Issazadeh-Navikas
View graph of relations

Familial Parkinson disease (PD) is associated with rare genetic mutations, but the etiology in most patients with sporadic (s)PD is largely unknown, and the basis for its progression to dementia (sPDD) is poorly characterized. We have identified that loss of IFNβ or IFNAR1, the receptor for IFNα/β, causes pathological and behavioral changes resembling PDD, prompting us to hypothesize that dysregulated genes in IFNβ-IFNAR signaling pathway predispose one to sPD. By transcriptomic analysis, we found defective neuronal IFNβ-IFNAR signaling, including particularly elevated PIAS2 associated with sPDD. With meta-analysis of GWASs, we identified sequence variants in IFNβ-IFNAR-related genes in sPD patients. Furthermore, sPDD patients expressed higher levels of PIAS2 mRNA and protein in neurons. To determine its function in brain, we overexpressed PIAS2 under a neuronal promoter, alone or with human α-synuclein, in the brains of mice, which caused motor and cognitive impairments and correlated with intraneuronal phosphorylated (p)α-synuclein accumulation and dopaminergic neuron loss. Ectopic expression of neuronal PIAS2 blocked mitophagy, increased the accumulation of senescent mitochondrial and oxidative stress, as evidenced by excessive oxDJ1 and 8OHdG, by inactivating ERK1/2-P53 signaling. Conversely, PIAS2 knockdown rescued the clinicopathological manifestations of PDD in Ifnb-/- mice on restoring mitochondrial homeostasis, oxidative stress, and pERK1/2-pP53 signaling. The regulation of JAK-STAT2-PIAS2 signaling was crucial for neurite outgrowth and neuronal survival and excitability and thus might prevent cognitive impairments. Our findings provide insights into the progression of sPD and dementia and have implications for new therapeutic approaches.

Original languageEnglish
JournalMolecular Psychiatry
Volume26
Issue number10
Pages (from-to)6083-6099
Number of pages17
ISSN1359-4184
DOIs
Publication statusPublished - Oct 2021

ID: 68339541