Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy.

Autonomous motivation promotes goal attainment through the conscious investment of effort, but mental contrasting with implementation intentions makes goal striving easier.

People with autonomous motives (e.g., personal importance) may use automated strategies to effortlessly sustain goal-directed behavior and overcome obstacles. We investigated whether conscious effort, ease of goal striving, physiological effort, and the number of obstacles encountered mediate relations between motives and goal attainment for a competitive cycling goal. Additionally, half the participants (n = 57) were trained in Mental Contrasting with Implementation Intentions (MCII) - a technique that facilitates development of goal-directed behavior - with remaining participants (n = 54) treated as controls. Conscious investment of effort mediated relations between autonomous motives and goal attainment. Subjective ease of goal striving and physiological effort did not. This result indicates that successful goal striving is not perceived as effortless for autonomously motivated individuals working on competitive goals. Conversely, MCII predicted a reduction in obstacles, which in turn was associated with easier goal striving but not goal attainment. Although MCII did not support goal attainment in the current study, its ability to minimize the influence of obstacles may still be useful for other types of goals or for sustaining long-term goal pursuit.