SCF ENCYCLOPEDIA ENTRY

TDP-43 PROTEINOPATHIES

SCF RNA-PROCESSING FAILURE & NEURONAL PROTEOSTASIS SYNCHRONIZATION COLLAPSE DOSSIER

I. OFFICIAL DISEASE CLASSIFICATION

TDP-43 Proteinopathies belong to SCF Clinical Domains C7 (Neurobiology), C1 (Genomic Medicine), C6 (Cellular Systems Biology), C5 (Metabolic Biology), and C15 (Neurodegenerative Disease Biology).

II. CLINICAL DEFINITION

TDP-43 Proteinopathies comprise a group of neurodegenerative disorders characterized by pathological accumulation of TDP-43 protein.

Primary associated diseases include:

• Amyotrophic Lateral Sclerosis
• Frontotemporal Dementia
• Limbic-predominant Age-related TDP-43 Encephalopathy
• Hippocampal sclerosis

Primary affected systems:

• Cerebral cortex
• Hippocampus
• Motor neurons
• Frontotemporal networks
• Spinal cord
• Synaptic systems

III. MAJOR CLASSIFICATIONS

A. ALS-TDP

B. FTLD-TDP

C. LATE

D. Mixed Neurodegenerative TDP-43 Disorders

Commonly coexist with:

• Alzheimer’s Disease
• Lewy Body Dementia

IV. CORE SCF ETIOPATHOGENIC THESIS

Within the Synergistic Compatibility Framework (SCF), TDP-43 Proteinopathies represent a systems-level collapse of:

• RNA-processing harmonics
• Nuclear-cytoplasmic transport fidelity
• Protein quality-control systems
• Synaptic maintenance networks
• Neuronal information-processing architecture

SCF interprets TDP-43 Proteinopathies as a neuroinformatic infrastructure failure in which a master regulator of RNA metabolism becomes unavailable to perform its normal functions while simultaneously generating toxic intracellular aggregates.

V. TDP-43 BIOLOGICAL FOUNDATION

Normal TDP-43 Function

TDP-43 normally regulates:

• RNA splicing
• RNA transport
• mRNA stability
• Stress responses
• Gene expression
• Synaptic maintenance

Associated concept:

• RNA splicing

Cellular Localization

Under normal conditions:

VI. MAJOR GENETIC CAUSES

Primary Genes

Associated concept:

• Proteostasis

VII. CORE PATHOPHYSIOLOGIC MECHANISMS

Hallmark Pathology

Classic findings:

• Cytoplasmic inclusions
• Hyperphosphorylated TDP-43
• Ubiquitinated aggregates
• Nuclear clearance of TDP-43

Associated concept:

• Protein aggregation

VIII. SCF FAULT ARCHITECTURE

IX. MULTI-OMICS PATHOGENESIS

A. Genomics

Affected pathways:

• RNA metabolism
• Protein degradation
• Autophagy
• Cellular stress regulation

B. Transcriptomics

Dysregulated pathways:

• Alternative splicing
• mRNA transport
• Synaptic gene regulation
• Neuroprotective signaling

C. Proteomics

Observed abnormalities:

• TDP-43 aggregates
• Ubiquitinated proteins
• Chaperone dysfunction
• Proteasomal stress markers

D. Neuroproteomics

Key dysfunction:

• Misfolded proteins
• Aggregate accumulation
• Proteostatic collapse
• Synaptic degeneration

E. Neuroinformaticomics (SCF)

Observed abnormalities:

• RNA signaling errors
• Information-processing bottlenecks
• Communication degradation
• Distributed network collapse

X. SCF PATHOGENESIS FLOW

Stage 1 — Molecular Trigger

Genetic, aging, or environmental stress initiates dysfunction.

Stage 2 — TDP-43 Mislocalization

Protein leaves nucleus and accumulates in cytoplasm.

Stage 3 — Aggregate Formation

Toxic inclusions develop.

Stage 4 — RNA Dysregulation

Gene-expression networks destabilize.

Stage 5 — Synaptic Failure

Neural communication deteriorates.

Stage 6 — Progressive Neurodegeneration

Clinical disease emerges.

XI. SYSTEMIC CONSEQUENCES

Associated conditions:

• Aphasia
• Executive dysfunction

XII. RHENOVA INTERPRETATION

Project RHENOVA interprets TDP-43 Proteinopathies as a neuroinformatic control-center collapse syndrome.

RHENOVA Dynamics

• Information-routing failures
• Regulatory bottlenecks
• Aggregate congestion
• Signal degradation
• Network collapse

RHENOVA Biomarkers

XIII. DBI INTERPRETATION

The SCF Decentralized Biological Intelligence framework interprets neurons as distributed information-processing systems.

Normal functions:

• Data storage
• Signal routing
• Adaptive processing
• Error correction
• Resource allocation

DBI Failure Features

• Regulatory corruption
• Information bottlenecks
• Processing delays
• Communication collapse

This transforms a resilient neural network into a progressively dysfunctional information-processing architecture.

XIV. CLINICAL MANIFESTATIONS

Motor Manifestations

• Muscle weakness
• Fasciculations
• Spasticity
• Paralysis

Associated condition:

• Motor neuron disease

Cognitive Manifestations

• Memory impairment
• Executive dysfunction
• Attention deficits

Associated condition:

• Mild cognitive impairment

Behavioral Manifestations

• Disinhibition
• Apathy
• Personality change
• Social dysfunction

Language Manifestations

• Aphasia
• Speech difficulties
• Semantic impairment

Associated condition:

• Primary progressive aphasia

XV. DIAGNOSTICS

Diagnostic Hallmarks

Proteostatic principle:

TDP\text{-}43\ Mislocalization \Rightarrow RNA\ Processing\ Failure

Cellular relationship:

Protein\ Aggregation \Rightarrow Neuronal\ Toxicity

Clinical consequence:

Synaptic\ Failure \Rightarrow Neurodegeneration

XVI. STANDARD OF CARE

Current Management

Treatment depends on associated disease phenotype.

Examples include:

ALS-associated Disease

• Riluzole
• Edaravone

FTD-associated Disease

• Behavioral symptom management
• Speech therapy
• Cognitive support

Supportive Care

• Physical therapy
• Occupational therapy
• Nutritional support
• Respiratory support when indicated

XVII. SCF-PCR THERAPEUTIC ARCHITECTURE

A. Preventative (PCR-P)

Goals:

• Early biomarker detection
• Genetic risk assessment
• Network preservation

B. Curative (PCR-C)

Goals:

• Restore TDP-43 homeostasis
• Prevent aggregation
• Normalize RNA processing

C. Restorative (PCR-R)

Goals:

• Preserve neuronal viability
• Enhance proteostasis
• Restore synaptic communication
• Re-establish neuroinformatic synchronization

XVIII. ETHNOBIOPROSPECTING TARGETS

Note: No botanical intervention has been proven to correct TDP-43 pathology. The following represent exploratory neuroprotective, autophagy-support, and proteostasis-related research domains.

Traditional Chinese Medicine

• Gastrodia elata
• Panax ginseng

Ayurveda

• Bacopa monnieri
• Withania somnifera

Vietnamese Thuốc Nam

• Centella asiatica
• Polyscias fruticosa

XIX. SCF API DISCOVERY TARGETS

High-Priority Molecular Targets

1. TDP-43 aggregation inhibitors
2. Nuclear import restoration therapies
3. RNA-splicing correction platforms
4. Autophagy-enhancement technologies
5. Proteostasis restoration systems
6. Neuroinflammation-modulating biologics
7. Neuroinformatic synchronization restoration technologies

XX. SCF LAYMAN’S SUMMARY

TDP-43 Proteinopathies are a group of neurodegenerative disorders in which the TDP-43 protein becomes misplaced and accumulates inside nerve cells. Normally, TDP-43 helps manage RNA processing and cellular communication. When it leaves the nucleus and forms toxic aggregates in the cytoplasm, neurons lose essential regulatory functions while simultaneously experiencing toxic stress. This contributes to diseases such as ALS, frontotemporal dementia, and age-related cognitive decline. SCF interprets TDP-43 Proteinopathies as a failure of the brain’s information-management and protein-recycling systems, leading to progressive breakdown of neuronal communication networks.

XXI. STRATEGIC RESEARCH PRIORITIES

1. TDP-43 aggregation-blocking therapeutics
2. RNA-processing restoration platforms
3. Nuclear-cytoplasmic transport correction technologies
4. Autophagy-enhancement systems
5. Proteostasis engineering approaches
6. Neuroinflammation-modulation therapies
7. Neuronal synchronization restoration strategies

MASTER REGISTRY INDEX

SCF-TDP43-0001 — TDP-43 Proteinopathies Master Registry

SCF-TDP43-RNA-0002 — RNA Processing Failure Layer

SCF-TDP43-AGGREGATION-0003 — Protein Aggregation Layer

SCF-TDP43-PROTEOSTASIS-0004 — Cellular Quality-Control Failure Layer

SCF-TDP43-RHENOVA-0005 — Neuroinformatic Infrastructure Collapse Layer

SCF-TDP43-DBI-0006 — Neural Information Processing Failure Layer

SCF-TDP43-PCR-0007 — Preventative–Curative–Restorative Layer