How neurons maintain their axons long-term: an integrated view of axon biology and pathology

Smith, Gaynor A.; Sweeney, Sean T.; O’Kane, Cahir J.; Prokop, Andreas

doi:10.3389/fnins.2023.1236815

Cited by 3 publications

(2 citation statements)

References 509 publications

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“…This work adds to the growing repertoire of CDKs to specifically regulate the size and function of neurons. It also demonstrates the importance of the actin cytoskeleton to prevent age-dependent neurodegeneration [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

Townsend,

Clarke,

Maddison

et al. 2023

Cell Death Discov.

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The role of cyclin-dependent kinases (CDKs) that are ubiquitously expressed in the adult nervous system remains unclear. Cdk12 is enriched in terminally differentiated neurons where its conical role in the cell cycle progression is redundant. We find that in adult neurons Cdk12 acts a negative regulator of actin formation, mitochondrial dynamics and neuronal physiology. Cdk12 maintains the size of the axon at sites proximal to the cell body through the transcription of homeostatic enzymes in the 1-carbon by folate pathway which utilize the amino acid homocysteine. Loss of Cdk12 leads to elevated homocysteine and in turn leads to uncontrolled F-actin formation and axonal swelling. Actin remodeling further induces Drp1-dependent fission of mitochondria and the breakdown of axon-soma filtration barrier allowing soma restricted cargos to enter the axon. We demonstrate that Cdk12 is also an essential gene for long-term neuronal survival and loss of this gene causes age-dependent neurodegeneration. Hyperhomocysteinemia, actin changes, and mitochondrial fragmentation are associated with several neurodegenerative conditions such as Alzheimer’s disease and we provide a candidate molecular pathway to link together such pathological events.

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Section: Discussionmentioning

confidence: 99%

Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

Townsend,

Clarke,

Maddison

et al. 2023

Cell Death Discov.

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“…Therefore, appropriate animal models, both for health and disease, are relevant. The understanding of the normal biology and the physiology of the neurons and the other key player cells under normal conditions and under stress are of crucial importance [168,169]. Animal studies should be combined with studies that also involve a variety of analyses in humans, e.g., diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and tractography [170] as well as neurophysiology [171].…”

Section: Conclusion and Significancementioning

confidence: 99%

The Dynamics of Nerve Degeneration and Regeneration in a Healthy Milieu and in Diabetes

Dahlin

2023

IJMS

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Appropriate animal models, mimicking conditions of both health and disease, are needed to understand not only the biology and the physiology of neurons and other cells under normal conditions but also under stress conditions, like nerve injuries and neuropathy. In such conditions, understanding how genes and different factors are activated through the well-orchestrated programs in neurons and other related cells is crucial. Knowledge about key players associated with nerve regeneration intended for axonal outgrowth, migration of Schwann cells with respect to suitable substrates, invasion of macrophages, appropriate conditioning of extracellular matrix, activation of fibroblasts, formation of endothelial cells and blood vessels, and activation of other players in healthy and diabetic conditions is relevant. Appropriate physical and chemical attractions and repulsions are needed for an optimal and directed regeneration and are investigated in various nerve injury and repair/reconstruction models using healthy and diabetic rat models with relevant blood glucose levels. Understanding dynamic processes constantly occurring in neuropathies, like diabetic neuropathy, with concomitant degeneration and regeneration, requires advanced technology and bioinformatics for an integrated view of the behavior of different cell types based on genomics, transcriptomics, proteomics, and imaging at different visualization levels. Single-cell-transcriptional profile analysis of different cells may reveal any heterogeneity among key players in peripheral nerves in health and disease.

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Metabolite profile in hereditary spastic paraplegia analyzed using magnetic resonance spectroscopy: a cross-sectional analysis in a longitudinal study

Montanaro,

Vavla,

Frijia

et al. 2024

Front. Neurosci.

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BackgroundHereditary Spastic Paraplegias (HSP) are genetic neurodegenerative disorders affecting the corticospinal tract. No established neuroimaging biomarker is associated with this condition.MethodsA total of 46 patients affected by HSP, genetically and clinically evaluated and tested with SPRS scores, and 46 healthy controls (HC) matched by age and gender underwent a single-voxel Magnetic Resonance Spectroscopy sampling (MRS) of bilateral pre-central and pre-frontal regions. MRS data were analyzed cross-sectionally (at T0 and T1) and longitudinally (T0 vs. T1).ResultsStatistically significant data showed that T0 mI/Cr in the pre-central areas of HSP patients was higher than in HC. In the left (L) pre-central area, NAA/Cr was significantly lower in HSP than in HC. In the right (R) pre-frontal area, NAA/Cr was significantly lower in HSP patients than in HC. HSP SPG4 subjects had significantly lower Cho/Cr concentrations in the L pre-central area compared to HC. Among the HSP subjects, non-SPG4 patients had significantly higher mI/Cr in the L pre-central area compared to SPG4 patients. In the R pre-frontal area, NAA/Cr was reduced, and ml/Cr was higher in non-SPG4 patients compared to SPG4 patients. Comparing “pure” and “complex” forms, NAA/Cr was higher in pHSP than in cHSP in the R pre-central and R pre-frontal areas. The longitudinal analysis, which involved fewer patients (n = 30), showed an increase in mI/Cr concentration in the L pre-frontal area among HSP subjects with respect to baseline. The patients had significantly higher SPRS scores at follow-up, with a significant positive correlation between SPRS scores and mI/Cr in the L pre-central area, while in bilateral pre-frontal areas, lower SPRS scores corresponded to higher NAA/Cr concentrations. To explore the discriminating power of MRS in correctly identifying HSP and controls, an inference tree methodology classified HSP subjects and controls with an overall accuracy of 73.9%, a sensitivity of 87.0%, and a specificity of 60.9%.ConclusionThis pilot study indicates that brain MRS is a valuable approach that could potentially serve as an objective biomarker in HSP.

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How neurons maintain their axons long-term: an integrated view of axon biology and pathology

Cited by 3 publications

References 509 publications

Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

Cdk12 maintains the integrity of adult axons by suppressing actin remodeling

The Dynamics of Nerve Degeneration and Regeneration in a Healthy Milieu and in Diabetes

Metabolite profile in hereditary spastic paraplegia analyzed using magnetic resonance spectroscopy: a cross-sectional analysis in a longitudinal study

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