GM1 and GM2 (Tay-Sachs and Sandhoff diseases) gangliosidoses are rare, autosomal recessive, potentially life-threatening, disabling disorders characterized by progressive neurodegeneration, with no disease-modifying treatment. This qualitative study aimed to understand the humanistic burden of GM1 and GM2 gangliosidoses from caregivers' perspectives by expanding knowledge on the day-to-day responsibilities of primary caregivers and the impacts experienced while providing care and support. Focus groups (90-minute duration) were conducted with caregivers (≥ 18 years) under three separate categories based on the age of the individuals with GM1/GM2 gangliosidoses either in-person (attending Annual National Tay-Sachs & Allied Diseases Association [NTSAD] Conference, Colorado, July 2022) or online (recruited through the NTSAD and Cure GM1 Foundation during November-December 2022). This study included 29 primary caregivers (mean [range] age: 49.0 [37.0-75.0] years) of individuals (children [24.1%], adolescents [31.0%], and adults [44.8%]) diagnosed with juvenile/late-onset GM1 (41.4%) or GM2 (58.6%) gangliosidoses. The caregivers reported that most individuals required mobility aids (64.3%) and experienced speech difficulties (83.3%); they described their caregiving responsibilities as non-stop, pervasive, and often done without additional support, with marginal variance by disease type or patient age. Supporting activities of daily living was the most prominent responsibility (90.0%), followed by symptom/care management (69.0%), ensuring quality of life (45.0%), and maintaining emotional (24.0%) and physical (10.0%) well-being. Caregiving impacted every facet of life; the caregivers reported 25 different impacts, with constant psychological burden (82.8%), physical ailments/strain (62.1%), anxiety/fear/worry (58.6%), financial difficulties (58.6%), limited time for other family members (55.2%), and limitations on relationships outside family (51.7%) having the most significant effects. The caregivers relied mostly on patient advocacy organizations for resources and expressed the need for financial support, broader disease awareness, and disease-modifying treatments. Although providing care and support deleteriously impacted caregivers' lives, they reported experiencing positive impacts on relationship building, personal development, family cohesion, community support, and life outlook. This study showed a substantial humanistic burden with long-term impacts among the caregivers of individuals with GM1 and GM2 gangliosidoses. The findings provide important insights to enhance clinical care while advocating for the resources needed to improve caregivers' and patients' lives.

Tay-Sachs disease (TSD) is a rare and severe neurodegenerative disorder inherited in an autosomal recessive manner. It is caused by a deficiency of the enzyme hexosaminidase A, which is responsible for the degradation of GM2 gangliosides-lipids that accumulate in the nerve cells of the central nervous system. The inability to break down these lipids leads to their progressive accumulation, resulting in irreversible brain damage. Mechanistically, TSD is caused by mutations in the HEXA gene, which encodes the alpha subunit of hexosaminidase A. These mutations disrupt enzyme activity and alter cellular pathways involved in lysosomal lipid degradation. Although Tay-Sachs specifically involves the alpha subunit, similar clinical features can be seen in Sandhoff disease, a related disorder caused by mutations in the HEXB gene, which encodes the beta subunit shared by hexosaminidase A and B. Tay-Sachs is classified into three clinical forms according to age of onset and symptom severity: the classic infantile form, which is the most common and severe; a juvenile (subacute) form; and an adult-onset form, which progresses more slowly and tends to present with milder symptoms. Diagnosis is based on enzymatic testing showing reduced or absent hexosaminidase A activity, confirmed by genetic testing. Prenatal diagnosis and genetic counseling play a key role in prevention and reproductive decision-making, especially in high-risk populations. Although no curative treatment currently exists, ongoing research is exploring gene therapy, enzyme replacement, and pharmacological approaches. Certain compounds, such as gemfibrozil, have shown potential to slow symptom progression. Early diagnosis and multidisciplinary care are essential to improving quality of life, although therapeutic options remain limited due to the progressive nature of the disease.

Sandhoff disease (SD) is a progressive neurodegenerative lysosomal storage disorder characterized by GM2 ganglioside accumulation as a result of mutations in the HEXB gene, which encodes the β-subunit of the enzyme β-hexosaminidase. Lysosomal storage of GM2 triggers inflammation in the CNS and periphery. The NLRP3 inflammasome is an important coordinator of pro-inflammatory responses, and we have investigated its regulation in murine SD. The NLRP3 inflammasome requires two signals, lipopolysaccharide (LPS) and ATP, to prime and activate the complex, respectively, leading to IL-1β secretion. Peritoneal, but not bone-marrow-derived, macrophages from symptomatic SD mice, but not those from pre-symptomatic animals, secrete the cytokine following priming with LPS with no requirement for activation with ATP, suggesting that such NLRP3 deregulation is related to the extent of glycosphingolipid storage. Dysregulated production of IL-1β was dependent upon caspase activity but not cathepsin B. We investigated the role of IL-1β in SD pathology using two approaches: the creation of hexb-/-Il1r1-/- double knockout mice or by treating hexb-/- animals with anakinra, a recombinant form of the IL-1 receptor antagonist, IL-1Ra. Both resulted in modest but significant extensions in lifespan and improvement of neurological function. These data demonstrate that IL-1β actively participates in the disease process and provides proof-of-principle that blockade of the pro-inflammatory cytokine IL-1β may provide benefits to patients.

GBA2, the non-lysosomal β-glucosylceramidase, is an enzyme involved in glucosylceramide metabolism. Pharmacological inhibition of GBA2 by N-alkyl iminosugars is well tolerated and benefits patients suffering from Sandhoff and Niemann-Pick type C diseases, and GBA2 inhibitors have been proposed as candidate-clinical drugs for the treatment of parkinsonism. With the ultimate goal to unravel the role of GBA2 in (patho)physiology, we sought to develop a GBA2-specific activity-based probe (ABP). A library of probes was tested for activity against GBA2 and the two other cellular retaining β-glucosidases, lysosomal GBA1 and cytosolic GBA3. We show that β-d-arabinofuranosyl cyclitol aziridine (β-d-Araf aziridine) reacts with the GBA2 active site nucleophile to form a covalent and irreversible bond. Fluorescent β-d-Araf aziridine probes potently and selectively label GBA2 both in vitro and in cellulo, allowing for visualization of the localization of overexpressed GBA2 using fluorescence microscopy. Co-staining with an antibody selective for the lysosomal β-glucosylceramidase GBA1, shows distinct subcellular localization of the two enzymes. We proffer our ABP technology for further delineating the role and functioning of GBA2 in disease and propose the β-d-Araf aziridine scaffold as a good starting point for the development of GBA2-specific inhibitors for clinical development.

Tay-Sachs disease (TSD) and its severe form Sandhoff disease (SD) are autosomal recessive lysosomal storage metabolic disorders, which often result into excessive GM2 ganglioside accumulation predominantly in lysosomes of nerve cells. Although patients with these diseases appear normal at birth, the progressive accumulation of undegraded GM2 gangliosides in neurons leads to early death accompanied by manifestation of motor difficulties and gradual loss of behavioral skills. Unfortunately, there is still no effective treatment available for TSD/SD. The present study highlights the importance of cinnamic acid (CA), a naturally occurring aromatic fatty acid present in a number of plants, in inhibiting the disease process in a transgenic mouse model of SD. Oral administration of CA significantly attenuated glial activation and inflammation and reduced the accumulation of GM2 gangliosides/glycoconjugates in the cerebral cortex of Sandhoff mice. Besides, oral CA also improved behavioral performance and increased the survival of Sandhoff mice. While assessing the mechanism, we found that oral administration of CA increased the level of peroxisome proliferator-activated receptor α (PPARα) in the brain of Sandhoff mice and that oral CA remained unable to reduce glycoconjugates, improve behavior and increase survival in Sandhoff mice lacking PPARα. Our results indicate a beneficial function of CA that utilizes a PPARα-dependent mechanism to halt the progression of SD and thereby increase the longevity of Sandhoff mice.