biostudies-literatureUnknownMattei DNCATS NIH HHSNIA NIH HHSNINDS NIH HHSNIH HHSMonocytes are increasingly implicated in Parkinson's disease (PD) pathogenesis, with idiopathic cases showing mitochondrial and lysosomal dysfunction. However, the impact of PD-associated mutations on monocytes remains unclear. To address this, we investigated transcriptomic and functional disturbances in peripheral monocytes from patients with <i>GBA1</i>- and <i>LRRK2</i>-associated PD and idiopathic PD. Transcriptomic data revealed shared and mutation-specific signatures, including those related to immune dysregulation, and consistent defects in lysosomal and mitochondrial pathways. Network and pathway analyses further uncovered downregulation in protein translation and enrichment of integrated stress response (ISR) signatures, alongside aberrant expression of genes linked to ER stress,medRxiv : the preprint server for health sciences2025.10.08.25337448https://www.ebi.ac.uk/biostudies/studies/S-EPMC12633084biostudies-literatureIntegrated Stress Response Signatures Drive Monocyte Dysfunction in &lt;i&gt;GBA1&lt;/i&gt;- and &lt;i&gt;LRRK2&lt;/i&gt;-Linked Parkinson's Disease.PMC12633084S10 OD030463R56 AG055824U01 NS094148S10 OD026880UL1 TR004419P30 AG066514S10 OD018522F31 NS134319R01 AG054005U54 NS123743U01 AG068880R21 AG063130U01 NS107016RF1 AG065926R01 NS133742R01 NS116006Riboldi GSwan MYoung CLeaver KMattei DMajos ONHumphrey JBressman SDomingo AMeijia ESaunders-Pullman RShanker VLWise ARaymond DFrucht SNavarro EKhashan TBrophy ERaj TRosen MJang BPullman MYang MKatsnelson VAllan AOrtega RChung AMuller BAstudillo KOzelius LJfalseIntegrated Stress Response Signatures Drive Monocyte Dysfunction in &lt;i&gt;GBA1&lt;/i&gt;- and &lt;i&gt;LRRK2&lt;/i&gt;-Linked Parkinson's Disease.Monocytes are increasingly implicated in Parkinson's disease (PD) pathogenesis, with idiopathic cases showing mitochondrial and lysosomal dysfunction. However, the impact of PD-associated mutations on monocytes remains unclear. To address this, we investigated transcriptomic and functional disturbances in peripheral monocytes from patients with <i>GBA1</i>- and <i>LRRK2</i>-associated PD and idiopathic PD. Transcriptomic data revealed shared and mutation-specific signatures, including those related to immune dysregulation, and consistent defects in lysosomal and mitochondrial pathways. Network and pathway analyses further uncovered downregulation in protein translation and enrichment of integrated stress response (ISR) signatures, alongside aberrant expression of genes linked to ER stress,2025-01-01T00:00:00Z2025 Oct2026-06-12T03:13:24.287Z2026-06-12T03:08:04.739ZS-EPMC126330844128271810.1101/2025.10.08.25337448