Proteinopathies, characterized by the misfolding, aggregation, and deposition of proteins, are hallmarks of various neurodegenerative and systemic diseases. Increasingly, research has highlighted the role of protein misfolding in parasitic infections, unveiling intricate interactions between host and parasite that exacerbate disease pathology and contribute to chronic outcomes. The life cycles of parasitic protozoa, including Plasmodium, Toxoplasmosis, and Leishmania species, are complicated and involve frequent changes between host and vector environments. Their proteomes are severely stressed during these transitions, which calls for highly specialized protein quality control systems. In order to survive harsh intracellular conditions during infection, these parasites have been demonstrated to display unique adaptations in the unfolded protein response, a crucial pathway controlling endoplasmic reticulum stress. In addition to improving parasite survival, these adaptations affect host cell signaling and metabolism, which may jeopardize cellular homeostasis. By causing oxidative stress, persistent inflammation, and disturbance of cellular proteostasis, host–parasite interactions also contribute to proteinopathy. For instance, Plasmodium falciparum disrupts normal protein homeostasis and encourages the accumulation of misfolded proteins by influencing host redox systems involved in protein folding. In addition to interfering with host chaperone systems, the parasitic secretion of effector proteins exacerbates protein misfolding and aggregate formation. Autophagy, apoptosis regulation, organelle integrity, and other vital cellular processes are all disrupted by these pathological protein aggregates. Long-term misfolding and aggregation can cause irreversible tissue damage, which can worsen the clinical course of illnesses like visceral leishmaniasis, cerebral malaria, and toxoplasmosis. Treating parasite-induced proteinopathies is a potentially fruitful area of therapy. According to recent research, autophagy modulators, proteasome enhancers, and small-molecule chaperones may be repurposed to lessen these effects. Pharmacological agents that target the UPR, for example, have demonstrated the ability to decrease parasite survival while also reestablishing host protein homeostasis. Targeting the proteins secreted by parasites that disrupt host proteostasis may also offer a novel way to stop tissue damage caused by proteinopathies. In conclusion, the intersection of protein misfolding and parasitic infections represents a rapidly advancing field of research. Dissecting the molecular pathways underpinning these processes offers unprecedented opportunities for developing innovative therapies. These insights could not only transform the management of parasitic diseases but also contribute to a broader understanding of proteinopathies in infectious and non-infectious diseases alike.

Background: Biallelic variants in SHQ1 (SHQ1 homolog; H/ACA small nucleolar ribonucleoprotein assembly factor) cause neurodevelopmental disorder with dystonia and seizures (NEDDS), but descriptions of spontaneous motor organization, functional communication, and rehabilitation-relevant abilities remain limited. Case: We present a boy with infantile-onset epileptic encephalopathy, dystonia, cerebellar atrophy, and asymmetric spasticity in whom trio WES identified two heterozygous SHQ1 variants in trans: the maternally inherited c.5T>C (p.Leu2Pro) variant and the paternally inherited c.828_831del (p.Asp277SerfsTer27) variant. Both SHQ1 variants remain classified as variants of uncertain significance (VUS) under ACMG criteria. Based on the available genetic evidence, including segregation in trans, and the close phenotypic concordance, SHQ1-related NEDDS is considered the most likely clinical diagnosis; however, the molecular findings do not independently establish the diagnosis. At 5 years and 4 months, assessment combined neurological and physiotherapeutic examination, Vojta-derived Locomotion Stages, and an adapted, descriptive item-level Bayley-4 assessment conducted outside the normative age range. The child independently expressed LS 3 creeping, brief ineffective homologous lower-limb attempts, supported kneeling with goal-directed upward reaching, and intentional tablet-based augmentative and alternative communication despite severe expressive and motor limitations. Observed task performance during the adapted Bayley-4 assessment was heterogeneous and was interpreted solely descriptively because chronological age exceeded the normative range and administration required accommodations. After adjunctive cannabidiol was introduced, prolonged nocturnal tonic seizures requiring rescue medication became less frequent and subsequently ceased, whereas focal seizures persisted during wakefulness and overall daily seizure frequency did not show a comparable reduction. Because this was a single, unblinded observation with concomitant antiseizure-medication changes and no prospectively predefined, directly comparable observation windows, no quantitative or causal treatment effect can be inferred. The available rehabilitation exposure was reconstructed retrospectively from parental report; detailed treatment progression and standardized longitudinal outcomes were not recorded prospectively. Conclusions: The present case broadens the functional phenotype of SHQ1-related NEDDS and shows that standardized developmental testing alone may underestimate communicative intentionality and functionally expressed abilities when motor output is severely constrained. Integrated functional assessment can refine phenotyping and identify individualized rehabilitation and assistive mobility targets. The assessment-informed physiotherapy framework is clinical and hypothesis-generating; it was not prospectively evaluated and should not be interpreted as evidence of treatment efficacy.