Department of Neurology, Brain Research Institute, Niigata University, Niigata, Niigata, 951-8585, Japan.
Department of System Pathology for Neurological Disorders, Brain Research Institute, Niigata University, Niigata, Japan.
Acta Neuropathol. 2023 Oct;146(4):611-629. doi: 10.1007/s00401-023-02615-8. Epub 2023 Aug 9.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，其特征在于皮质和脊髓运动神经元中存在 TDP-43 包含物。目前尚不清楚致病性 TDP-43 是否以及如何通过神经连接传播，从而使皮质脊髓运动回路中的退行性过程进展。在这里，我们建立了新的小鼠 ALS 模型，该模型最初在运动回路中的特定神经元或细胞类型中诱导突变 TDP-43 包含物，并研究了 TDP-43 和相关病理过程是否通过神经元或细胞连接传播。我们首先通过使用表达突变 TDP-43 的腺相关病毒（AAV），开发了主要在皮质脊髓神经元、脊髓运动神经元或前肢骨骼肌中诱导 TDP-43 包含物的 ALS 模型。我们发现，沿轴突顺行运输到皮质脊髓束（CST）中的少突胶质细胞中的 TDP-43 与轻度轴突变性同时发生。相比之下，引入脊髓运动神经元中的 TDP-43 不会逆行传播到皮质或脊髓神经元；但是，它会诱导脊髓运动神经元的极度丧失和随后相邻脊髓神经元的变性，表明在脊髓中以逆行方式发生退行性传播。脊髓内变性进一步导致严重的肌肉萎缩。最后，在骨骼肌中诱导的 TDP-43 不会逆行传播病理事件至脊髓神经元。我们的数据表明，突变 TDP-43 在皮质脊髓通路上沿神经胶质连接顺行传播，而在脊髓回路中则表现出不同的逆行退行性特征。这表明致病性 TDP-43 可能在 ALS 中引起运动系统中不同的顺行和逆行退行性机制。
