Dear Shraddha Srivastava

The question of whether a unified molecular mechanism connects genetic and sporadic ALS-FTD is a central focus of current research. While no single mechanism fully explains all cases, emerging evidence suggests converging pathways involving RNA metabolism, protein homeostasis, and non-coding regulatory elements. Here are key insights from recent studies:

1. RNA-Binding Proteins (RBPs) and Stress Granule Dynamics

TDP-43, FUS, and other RBPs: Both familial (e.g., TARDBP, FUS) and sporadic ALS-FTD cases exhibit cytoplasmic mislocalization and aggregation of TDP-43, suggesting a shared pathology. These proteins regulate RNA splicing, stability, and transport, and their dysfunction disrupts neuronal RNA metabolism.

Stress Granule (SG) Dysregulation: Persistent stress granules, which are RNA-protein assemblies formed during cellular stress, may seed pathological aggregates. Familial mutations (e.g., in C9orf72, FUS) impair SG dynamics, but sporadic cases also show similar SG abnormalities, implicating a common pathway.

2. Non-Coding Regions and Regulatory RNAs

C9orf72 Repeat Expansions: The GGGGCC repeat in C9orf72 (the most common genetic cause of ALS-FTD) produces toxic dipeptide repeats (DPRs) and aberrant RNA foci. Importantly, repeat-associated non-AUG (RAN) translation and RNA-mediated toxicity may also play roles in sporadic cases with cryptic repeat expansions.

Altered Non-Coding RNA Networks:

MicroRNAs (miRNAs): Dysregulation of miRNAs (e.g., miR-155, miR-132) is observed in both genetic and sporadic ALS-FTD, affecting neuroinflammation and synaptic function.

Long Non-Coding RNAs (lncRNAs): NEAT1, a lncRNA essential for paraspeckle formation, is upregulated in ALS-FTD and may contribute to TDP-43 pathology. Other lncRNAs (e.g., MALAT1, *C9orf72-AS1*) are also implicated in RNA processing and nuclear export defects.

Enhancer and Splicing Dysregulation: Epigenomic studies reveal altered enhancer activity in sporadic ALS-FTD, particularly in genes involved in neuronal survival and RNA processing. Single-cell RNA-seq has identified aberrant splicing patterns shared between familial and sporadic cases.

3. Converging Pathways from Omics Studies

Transcriptomics: Co-expression networks from post-mortem tissues highlight disruptions in RNA processing, autophagy, and neuroinflammation across both genetic and sporadic cases.

Epigenomics: DNA methylation changes in sporadic ALS-FTD often affect genomic regions controlling TARDBP, FUS, and GRN, suggesting epigenetic mimicry of genetic mutations.

Single-Cell Analyses: Neuronal subtypes vulnerable in ALS-FTD (e.g., cortical layer 5b neurons, motor neurons) show convergent transcriptional signatures, including upregulation of *TDP-43* targets and downregulation of synaptic genes.

4. Potential Unifying Mechanisms

Disrupted Nucleocytoplasmic Transport: Both C9orf72 mutations and sporadic TDP-43 pathology impair nuclear pore function, leading to mRNA export defects.

Prion-like Propagation of Pathology: Misfolded TDP-43 may spread in a prion-like manner, even in sporadic cases, suggesting a shared pathogenic cascade.

Endolysosomal and Autophagy Defects: GRN mutations cause progranulin deficiency, impairing lysosomal function, while sporadic cases show similar autophagic disruptions.

While no single mechanism explains all ALS-FTD cases, dysregulation of RNA metabolism, stress granule dynamics, and non-coding RNAs (e.g., lncRNAs, miRNAs) appear to be a unifying theme. Sporadic cases may arise from a combination of environmental triggers, somatic mutations, and epigenetic changes that converge on the same pathways disrupted by genetic mutations. Advances in single-cell multi-omics and CRISPR-based screens are expected to further clarify these connections.

1. Non-Coding RNAs (ncRNAs) as Key Players in ALS-FTD Pathogenesis

A. Long Non-Coding RNAs (lncRNAs)

• NEAT1: Essential for paraspeckle formation, a nuclear body that sequesters RNAs and proteins under stress. Upregulated in ALS-FTD and interacts with TDP-43, potentially contributing to its aggregation. It may compensate for the nuclear loss of TDP-43 by trapping misfolded RNAs.
• MALAT1: Regulates alternative splicing and synaptic function. Depletion in neurons leads to TDP-43 mislocalization, suggesting a feedback loop.
• C9orf72-AS1 (antisense RNA): Produced from the C9orf72 locus and may regulate the sense GGGGCC repeat transcript. Could modulate RAN translation or RNA foci toxicity in both repeat-expansion and sporadic cases.

B. MicroRNAs (miRNAs)

• miR-155: Upregulated in ALS-FTD, linked to neuroinflammation (activates microglia). Targets *TDP-43* and FUS, creating a feedback loop.
• miR-132: Downregulated in sporadic ALS-FTD, leading to neuronal hyperexcitability. Regulates *TDP-43* and SIRT1 (a neuroprotective factor).

C. Circular RNAs (circRNAs)

• Accumulate in ALS-FTD due to TDP-43-mediated splicing defects.
• Some circRNAs (e.g., *circ-Hdgfrp3*) act as sponges for miRNAs, altering RNA homeostasis.

2. Epigenetic Dysregulation as a Unifying Mechanism

A. DNA Methylation Changes

• Hypermethylation of C9orf72 promoter: Seen in some sporadic ALS cases, mimicking the loss-of-function seen in C9orf72 mutation carriers.
• Hypomethylation of retrotransposons: *LINE-1* activation in sporadic ALS-FTD may drive genomic instability and neurotoxicity.

B. Histone Modifications & Chromatin Remodeling

• H3K27ac (active enhancer mark): Altered in motor neurons of sporadic ALS, affecting neurodegeneration-linked enhancers.
• HDAC inhibitors (e.g., sodium phenylbutyrate) show promise in clinical trials, suggesting epigenetic therapy could benefit both genetic and sporadic cases.

C. Somatic Mutations & Mosaicism

• Emerging evidence suggests low-frequency somatic mutations in TARDBP, FUS, or GRN could explain some sporadic cases.
• Single-cell sequencing may reveal hidden genetic contributions in "sporadic" patients.

3. Therapeutic Implications & Convergence Points

A. Targeting RNA Metabolism

• Antisense Oligonucleotides (ASOs): In trials for C9orf72 (targeting GGGGCC repeats) and SOD1 ALS. Could be adapted for toxic lncRNAs (e.g., NEAT1 suppression).
• Small Molecules to Dissolve Stress Granules: Compounds like ISRIB (integrated stress response inhibitor) rescue TDP-43 toxicity in models.

B. Modifying ncRNA Networks

• miRNA mimics/inhibitors: e.g., anti-miR-155 to reduce neuroinflammation.
• CRISPR-based lncRNA editing: Could be used to delete or modulate NEAT1 or *C9orf72-AS1*.

C. Boosting Autophagy/Lysosomal Function

• Since GRN mutations and sporadic TDP-43 cases both impair lysosomes: TFEB activators (e.g., trehalose) enhance the clearance of aggregates. Progranulin-boosting therapies (e.g., TMEM106B inhibitors) may help sporadic cases with low progranulin.

4. Open Questions & Future Directions

• Do cryptic repeat expansions exist in sporadic ALS-FTD? Some patients without C9orf72 expansions show similar RNA foci—could other repeats (e.g., NOTCH2NLC) be involved?
• How much do somatic mutations contribute to sporadic cases?
• Can we identify "epigenetic signatures" that predict sporadic ALS-FTD progression?

Final Takeaway

While TDP-43 pathology and RNA dysregulation are central to both genetic and sporadic ALS-FTD, non-coding RNAs and epigenetic changes appear to be critical convergence points. Targeting these pathways (e.g., with ASOs, miRNA modulators, or HDAC inhibitors) could lead to broad-spectrum therapies applicable across ALS-FTD subtypes.