Lysosomal Diseases and Neuropsychiatry: Opportunities to Rebalance the Mind

Abstract

The brain is the physical organ of the mind but efforts to understand mental illness within a neurobiological context have hitherto been unavailing. Mental disorders (anxiety, depression, bipolar disorder, and schizophrenia) affect about one fifth of the population and present an almost endless societal challenge at the frontier of human sciences. Prodigious technological advances in functional neuroimaging and large-scale genetics have not yet delivered the prospect of refined molecular understanding of mental illness beyond early anatomical descriptions of brain metabolism. However, intensive clinical phenotyping and quantitative metabolic studies using sophisticated radio-ligands in positron-emission tomography, persistently favor the neurobiological approach. This Perspective pursues a familiar maxim in Medicine, aptly summarized in the words of Arthur Koestler: "Nature is generous in her senseless experiments on mankind." Hitherto, studies in neuropsychiatry have largely ignored rare genetic disorders but derangements of specific components within the cerebral laboratory offer rich opportunities for mechanistic exploration. Aberrant psychic behavior is characteristic of many inborn errors of metabolism and although each disorder represents a universe of its own, we are at a threshold for understanding, since contemporary genetics and cell biology furnish abundant materials to take on the perturbing enigma of mental derangement. A further development relates to orphan drugs with actions on defined molecular targets: these represent new ways to study the pathogenesis of psychiatric phenomena associated with rare diseases and in a manner not formerly possible. Here we introduce the frontier of schizophrenia and its strong association with late-onset Tay-Sachs disease as a paradigm to explore.

The GM2 gangliosidoses: Unlocking the mysteries of pathogenesis and treatment

“…Acute psychosis in the setting of LOSD is extremely rare or unreported. [ 29 , 42 ]. Retrospective developmental history review of patients with late-onset GM2 gangliosidoses and comparison to those of unaffected siblings or peers often uncovers subtle deficits emerging earlier in life.…”

“…Sensory symptoms and dysautonomia are reported to occur early in some patients with LOSD but are rarely or never a presenting symptom of for LOTS. Symptoms include distal painful burning, acroparesthesia worsened by heat and exercise, sensory loss, and overt dysautonomia from small diameter fiber sensory neuropathy [ 42 – 47 ]. Clinical and electrophysiological evidence of often asymptomatic peripheral neuropathy, elicited at the time of neurological examination (diminished sense to light touch, temperature or vibration) was present in 9/30 (27%) of patients with LOTS [ 48 ].…”

CRISPR-Cas9 Knock-In of T513M and G41S Mutations in the Murine β–Galactosyl-Ceramidase Gene Re-capitulates Early-Onset and Adult-Onset Forms of Krabbe Disease

“…This late-onset lysosomal response may undermine cellular functions in GALC G 41 S/G 41 S mutant neurons and lead to -some- of the observed alterations in exploratory behavior in these mice. Clinical manifestations affecting behavior and cognition have been described in several inborn errors of the metabolism ( Gutschalk et al, 2004 ; Cox, 2020 ). Whether the GALC G 41 S mutation, and perhaps others, affecting the GALC gene directly or indirectly impact the structure and/or activity of synapses of neural networks involved in higher cognitive functions remains an open question ( Castelvetri et al, 2011 ; Cantuti Castelvetri et al, 2013 ; Cantuti-Castelvetri and Bongarzone, 2016 ; Marshall and Bongarzone, 2016 ; Gowrishankar et al, 2020 ; Rebiai et al, 2021 ) and is the subject of a follow up study in our laboratories.…”

Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer’s Disease and Other Neurodegenerative Diseases

“…LSD includes different diseases that affect SL metabolism, such as Niemann-Pick’s disease, Gaucher’s disease, Farber’s disease, Krabbe’s disease, and Fabry’s disease. Given that part of the SLs is degraded in lysosomes, one of the key hallmarks of these diseases is neurodegeneration caused by SL metabolism alterations [ 31 , 124 , 125 ]. Niemann-Pick’s is a genetic disease caused by mutations in the SMPD1 gene (generating a deficiency of aSMase leading to a progressive accumulation of SM in the organs, including the brain); or in the NPC intracellular cholesterol transporter ( NPC1 or NPC2) genes (leading to alterations in cellular cholesterol trafficking) [ 126 ].…”