Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. As previous therapeutic trials in ALS have been severely hampered by patients’ heterogeneity, the identification of biomarkers that reliably reflect disease progression represents a priority in ALS research. Here, we used the D50 disease progression model to investigate correlations between cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels and disease aggressiveness. The D50 model quantifies individual disease trajectories for each ALS patient. The value D50 provides a unified measure of a patient’s overall disease aggressiveness (defined as time taken in months to lose 50% of functionality). The relative D50 (rD50) reflects the individual disease covered and can be calculated for any time point in the disease course. We analyzed clinical data from a well-defined cohort of 156 patients with ALS. The concentration of NfL in CSF samples was measured at two different laboratories using the same procedure. Based on patients’ individual D50 values, we defined subgroups with high (<20), intermediate (20–40), or low (>40) disease aggressiveness. NfL levels were compared between these subgroups via analysis of covariance, using an array of confounding factors: age, gender, clinical phenotype, frontotemporal dementia, rD50-derived disease phase, and analyzing laboratory. We found highly significant differences in NfL concentrations between all three D50 subgroups (p < 0.001), representing an increase of NfL levels with increasing disease aggressiveness. The conducted analysis of covariance showed that this correlation was independent of gender, disease phenotype, and phase; however, age, analyzing laboratory, and dementia significantly influenced NfL concentration. We could show that CSF NfL is independent of patients’ disease covered at the time of sampling. The present study provides strong evidence for the potential of NfL to reflect disease aggressiveness in ALS and in addition proofed to remain at stable levels throughout the disease course. Implementation of CSF NfL as a potential read-out for future therapeutic trials in ALS is currently constrained by its demonstrated susceptibility to (pre-)analytical variations. Here we show that the D50 model enables the discovery of correlations between clinical characteristics and CSF analytes and can be recommended for future studies evaluating potential biomarkers.

Aging is a complex process characterized by several molecular and cellular imbalances. The composition and stability of the neuronal cytoskeleton is essential for the maintenance of homeostasis, especially in long neurites. Using human skin biopsies containing sensory axons from a cohort of healthy individuals, we investigate alterations in cytoskeletal content and sensory axon caliber during aging via quantitative immunostainings. Cytoskeletal components show an increase with aging in both sexes, while elevation in axon diameter is only evident in males. Transcriptomic data from aging males illustrate various patterns in gene expression during aging. Together, the data suggest gender-specific changes during aging in peripheral sensory axons, possibly influencing cytoskeletal functionality and axonal caliber. These changes may cumulatively increase susceptibility of aged individuals to neurodegenerative diseases.

Derailed signaling originating from the plasma membrane is associated with many types of cancer. Mutations in ANKRD26 have been linked to different human cancers and to thrombocytopenia. These mutations include an N-terminal truncation associated with acute myeloid leukemia (AML). We conducted an initial characterization of Ankrd26's protein properties and unveil that an N-terminal amphipathic structure of Ankrd26 lacking in the AML-associated mutant is critical for membrane binding and for Ankrd26's ability to bend membranes by partial membrane insertion. Another Ankrd26 mutation linked to papillary thyroid carcinoma includes truncation and fusion with the kinase domain of the protooncogene RET. Our characterization of Ankrd26 properties reveals that the Ankrd26 part in the Ankrd26-RET fusion mutant is able to anchor the RET kinase domain to the plasma membrane and to mediate self-association - a function we demonstrate to be mediated by Ankrd26's coiled coil domain. Ankrd26-RET fusion led to a massive increase in RET autophosphorylation, i.e. to aberrant RET signaling. Understanding the molecular mechanistic properties of Ankrd26 thus provides important insights into Ankrd26-associated pathomechanisms in human cancer patients.

No abstract