Mutating ubiquitin carboxy terminal hydrolase L1 cysteine 152 ameliorates white matter injury and functional deficits in experimental vascular dementia

Vascular cognitive impairment and dementia (VCID) is characterized by extensive subcortical white matter injury and progressive sensorimotor and cognitive impairment. Post-translational modification of UCHL1 at cysteine 152 (C152) impairs repair of white matter injury and recovery of function after ischemia. We hypothesized that mutation of UCHL1 C152 would ameliorate white matter injury and cognitive impairment in VCID.

VCID was produced using the asymmetric bilateral common carotid artery stenosis (ABCS) model in young and 18-month-old mice bearing a UCHL1 cysteine 152 to alanine mutation (C152A) and wild-type (WT) controls. White matter injury was assessed using diffusion tensor imaging (DTI) and immunohistochemistry. Sensorimotor function was assessed using adhesive tape removal test.

Cognitive function was assessed by Morris water maze, passive avoidance, and novel object recognition tests. C152A mice exhibited reduced white matter injury as detected by DTI and improved performance on both sensorimotor and cognitive tests compared to WT mice in both young and 18-month-old groups. These results suggest that post-translational modification of UCHL1 cysteine 152 is important in the pathogenesis of white matter injury and functional impairment in VCID.

Therapeutic strategies aimed at preventing post-translational modification of UCHL1 C152 could reduce white matter injury and improve cognitive function in VCID. MRI was performed at the Advanced Imaging Center (RRID:SCR_025139), a core research facility, partially supported by the office of the Senior Vice Chancellor for Health Sciences at the University of Pittsburgh This work was supported by NIH NINDS and NIA [RF1NS037459 and R01NS102195 to S.H.G., R01 NS11750 to G. C.] and the Department of Veterans Affairs (BX006454 to G.C.).

The funding source had no role in study design, collection, analysis, and interpretation of data or in the writing of the report and the decision to submit the article for publication. Department of Neurology, School of Medicine, University of Pittsburgh, 200 Lothrop St, Room# S517 SBST, Pittsburgh, PA, 15213, USA Zhiping Mi, Dennis J. Zeh, Jie Ma, Zhongfang Weng, Madeline G.

Rose, Guodong Cao & Steven H. Graham Animal Imaging Center, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, 15213, USA Correspondence to Guodong Cao or Steven H. The authors declare no competing interest.