Three Studies Uncover New Genetic Mechanisms Behind Rare Neurological Disorders

A research team in Bochum and Tübingen has identified disease-causing variants of the gene CD99L2 as the cause of X-linked spastic ataxia. The researchers examined 2,811 patients with ataxia, hereditary spastic paraplegia, and dystonia. The findings were published in Nature Communications on February 14, 2026.

CD99L2 was primarily known for its functions in the immune system, but no role in the nervous system had previously been described. The researchers in Bochum demonstrated that the protein coded by CD99L2 acts as an activating partner for the calcium-dependent protease CAPN1, a known disease protein in spastic paraplegia and ataxia. Disease-causing variants lead to disrupted production of the CD99L2 protein in the cell and prevent its interaction with CAPN1. Patients' cells also showed specific disruptions of synaptic processes. The reduced CAPN1 activation and the resulting dysregulation of neuronal signal pathways plausibly explain the observed symptoms.

In a separate study published in Cell Reports Medicine, researchers identified protein phosphatase 2 regulatory subunit B'β (PPP2R5C) as a potential early biomarker associated with Alzheimer's disease. The discovery cohort included 4 cognitively normal individuals, 4 presymptomatic familial AD participants, and 5 familial AD patients. Label-free proteomic analysis showed that a PPP2R5C-specific peptide progressively decreased from presymptomatic FAD to FAD compared with cognitively normal controls.

Plasma PPP2R5C levels were approximately 61.3% lower in amnestic mild cognitive impairment and 31.6% lower in AD than in cognitively normal controls. The AD group exhibited 52.1% lower plasma PPP2R5C than the aMCI group. Plasma PPP2R5C distinguished AD from CN controls with an area under the receiver operating characteristic curve of 0.8494 and differentiated aMCI from controls with an AUROC of 0.7360. Plasma PPP2R5C was positively associated with Mini-Mental State Examination scores and negatively correlated with plasma phosphorylated tau 181, p-tau217, and p-tau231 levels, supporting relevance to tau pathology.

Postmortem brain analyses revealed lower PPP2R5C levels in aged AD patients compared with young CN and aged CN individuals, suggesting aging alone does not substantially reduce PPP2R5C expression. Immunohistochemical staining of Braak-graded AD brain samples showed PPP2R5C expression decreased as early as Braak stage II, when neurofibrillary tangles were still relatively limited.

Co-immunoprecipitation experiments demonstrated interaction between PPP2R5C and tau. Increasing PPP2R5C expression reduced phosphorylated tau and total tau levels while enhancing PP2A enzymatic activity. Silencing PPP2R5C decreased PP2A activity, suggesting a regulatory role rather than a purely correlative association. Pharmacological inhibitor experiments indicated PPP2R5C-driven tau degradation was blocked by autophagy-lysosome inhibitors, including chloroquine, leupeptin, and ammonium chloride, but not by the proteasome inhibitor MG132.

A third study published in Nature Genetics reveals that repeat expansions long thought to sit in noncoding DNA actually produce toxic proteins that drive several rare muscle and neurodegenerative diseases. The study centers on expansions of a short DNA sequence—GGC—repeated dozens to hundreds of times in tandem. These mutations are part of a larger class of genetic changes known as microsatellite repeat expansions, which cause over 60 disorders.

The conditions linked to these mutations include oculopharyngodistal myopathy (OPDM), a rare adult-onset muscle disorder marked by drooping eyelids, difficulty moving the eyes, swallowing problems, and progressive weakness of facial and distal limb muscles. A related disorder, oculopharyngeal myopathy with leukoencephalopathy (OPML), combines similar muscle symptoms with degeneration of brain white matter. Neuronal intranuclear inclusion disease (NIID) primarily affects the nervous system and can cause tremor, ataxia, neuropathy, cognitive changes, and muscle weakness. Although clinically distinct, these disorders share GGC repeat expansions in genes such as GIPC1, RILPL1 and NOTCH2NLC.

The study, a collaborative effort primarily between researchers at Université de Strasbourg and Peking University First Hospital, shows that the GGC repeats are embedded within previously unrecognized open reading frames—short stretches of RNA capable of being translated into protein. When the GGC repeat expands beyond roughly 50 copies, the sequence is translated into a long chain of glycine amino acids. Because each GGC codon encodes glycine, the mutation generates polyglycine, or polyG, proteins.

These expanded polyG proteins are stable and prone to aggregation. In muscle biopsies from people with OPDM and OPML, researchers detected the newly identified polyG proteins within hallmark and rimmed vacuoles and rare eosinophilic intranuclear inclusions, which are p62-positive and ubiquitin-positive but of unknown origin and composition. Similar inclusions appear in the nervous system in NIID patients.

Experiments in cultured human muscle cells demonstrated that expressing expanded polyG proteins leads to the formation of cytoplasmic and nuclear aggregates and ultimately to cell death. Importantly, repeat-containing RNA that was engineered so it could not be translated into protein was not toxic, strongly indicating that the protein product—not the RNA alone—is the primary driver of disease.

Mice engineered to express polyG proteins in skeletal muscle developed progressive muscle fiber atrophy and accumulated p62-positive inclusions that resemble those seen in patients. When expressed in the central nervous system, the proteins triggered neuroinflammation, loss of cerebellar Purkinje cells, impaired motor coordination, and shortened lifespan—features consistent with NIID.

Researchers identified a small molecule called TMPyP4—a cationic porphyrin known to also inhibit human telomerase and stacks with G tetrads to stabilize quadruplex DNA—that binds GC-rich sequences and reduces production and aggregation of polyG proteins in cells and fruit fly models. By interfering with translation of the expanded repeats, the compound offers proof of principle that targeting repeat-driven protein synthesis could mitigate disease.