Targeting neurological abnormalities in lysosomal storage diseases

Raquel van Gool; Anthony Tucker-Bartley; Edward Yang; Nicholas Todd; Frank Guenther; Benjamin Goodlett; Walla Al-Hertani; Olaf A Bodamer; Jaymin Upadhyay

doi:10.1016/j.tips.2021.11.005

Targeting neurological abnormalities in lysosomal storage diseases

Trends Pharmacol Sci. 2022 Jun;43(6):495-509. doi: 10.1016/j.tips.2021.11.005. Epub 2021 Nov 27.

Authors

Raquel van Gool¹, Anthony Tucker-Bartley², Edward Yang³, Nicholas Todd⁴, Frank Guenther⁵, Benjamin Goodlett⁶, Walla Al-Hertani⁶, Olaf A Bodamer⁶, Jaymin Upadhyay⁷

Affiliations

¹ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Faculty of Psychology and Neuroscience, Section Neuropsychology & Psychopharmacology, Maastricht University, Maastricht, The Netherlands.
² Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Department of Anesthesia, Critical Care and Pain Medicine, Harvard Medical School, Boston, MA, USA.
³ Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Department of Speech, Language and Hearing Sciences, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA, USA.
⁶ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁷ Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA. Electronic address: jaymin.upadhyay@childrens.harvard.edu.

PMID: 34844772
DOI: 10.1016/j.tips.2021.11.005

Abstract

Central nervous system (CNS) abnormalities and corresponding neurological and psychiatric symptoms are frequently observed in lysosomal storage disorders (LSDs). The genetic background of individual LSDs is indeed unique to each illness. However, resulting defective lysosomal function within the CNS can transition normal cellular processes (i.e., autophagy) into aberrant mechanisms, facilitating overlapping downstream consequences including neurocircuitry dysfunction, neurodegeneration as well as sensory, motor, cognitive, and psychological symptoms. Here, the neurological and biobehavioral phenotypes of major classes of LSDs are discussed alongside therapeutic strategies in development that aim to tackle neuropathology among other disease elements. Finally, focused ultrasound blood-brain barrier opening is proposed to enhance therapeutic delivery thereby overcoming the key hurdle of central distribution of disease modifying therapies in LSDs.

Keywords: autophagy; central nervous system abnormalities; lysosomal storage disease; neurological symptoms; psychiatric symptoms.

Publication types

Review

MeSH terms

Autophagy
Blood-Brain Barrier
Central Nervous System Diseases*
Humans
Lysosomal Storage Diseases* / drug therapy
Lysosomal Storage Diseases* / genetics
Lysosomes