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"Karsten, Peter"
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TDP-43-Mediated Neuron Loss In Vivo Requires RNA-Binding Activity
Alteration and/or mutations of the ribonucleoprotein TDP-43 have been firmly linked to human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The relative impacts of TDP-43 alteration, mutation, or inherent protein function on neural integrity, however, remain less clear--a situation confounded by conflicting reports based on transient and/or random-insertion transgenic expression. We therefore performed a stringent comparative investigation of impacts of these TDP-43 modifications on neural integrity in vivo. To achieve this, we systematically screened ALS/FTLD-associated and synthetic TDP-43 isoforms via same-site gene insertion and neural expression in Drosophila; followed by transposon-based motor neuron-specific transgenesis in a chick vertebrate system. Using this bi-systemic approach we uncovered a requirement of inherent TDP-43 RNA-binding function--but not ALS/FTLD-linked mutation, mislocalization, or truncation--for TDP-43-mediated neurotoxicity in vivo.
Journal Article
The Mitochondrial Chaperone Protein TRAP1 Mitigates α-Synuclein Toxicity
Overexpression or mutation of α-Synuclein is associated with protein aggregation and interferes with a number of cellular processes, including mitochondrial integrity and function. We used a whole-genome screen in the fruit fly Drosophila melanogaster to search for novel genetic modifiers of human [A53T]α-Synuclein-induced neurotoxicity. Decreased expression of the mitochondrial chaperone protein tumor necrosis factor receptor associated protein-1 (TRAP1) was found to enhance age-dependent loss of fly head dopamine (DA) and DA neuron number resulting from [A53T]α-Synuclein expression. In addition, decreased TRAP1 expression in [A53T]α-Synuclein-expressing flies resulted in enhanced loss of climbing ability and sensitivity to oxidative stress. Overexpression of human TRAP1 was able to rescue these phenotypes. Similarly, human TRAP1 overexpression in rat primary cortical neurons rescued [A53T]α-Synuclein-induced sensitivity to rotenone treatment. In human (non)neuronal cell lines, small interfering RNA directed against TRAP1 enhanced [A53T]α-Synuclein-induced sensitivity to oxidative stress treatment. [A53T]α-Synuclein directly interfered with mitochondrial function, as its expression reduced Complex I activity in HEK293 cells. These effects were blocked by TRAP1 overexpression. Moreover, TRAP1 was able to prevent alteration in mitochondrial morphology caused by [A53T]α-Synuclein overexpression in human SH-SY5Y cells. These results indicate that [A53T]α-Synuclein toxicity is intimately connected to mitochondrial dysfunction and that toxicity reduction in fly and rat primary neurons and human cell lines can be achieved using overexpression of the mitochondrial chaperone TRAP1. Interestingly, TRAP1 has previously been shown to be phosphorylated by the serine/threonine kinase PINK1, thus providing a potential link of PINK1 via TRAP1 to α-Synuclein.
Journal Article
DETECTING GOOD PUBLIC POLICY RATIONALES FOR THE AMERICAN RULE: A RESPONSE TO THE ILL-CONCEIVED CALLS FOR \LOSER PAYS\ RULES
Several critiques have been leveled at the American Rule—that is, the rule that each party to a lawsuit should pay for its attorneys. Some claim that there were no principled justifications offered by the nineteenth-century jurists who authored the opinions marking the rule's origins. Instead, these jurists only cited their states' \"taxable costs\" statutes. Others claim that the American Rule—as well as its close relative, the contingency-fee contract—contributed to a \"liability explosion\" in that century. This Article offers a comprehensive examination of the origins of, rationales given for, and impact of the American Rule; then it evaluates instances in which the rule has faced legislative, judicial, and academic opposition.
Journal Article
Large-Scale Screen for Modifiers of Ataxin-3-Derived Polyglutamine-Induced Toxicity in Drosophila
Polyglutamine (polyQ) diseases represent a neuropathologically heterogeneous group of disorders. The common theme of these disorders is an elongated polyQ tract in otherwise unrelated proteins. So far, only symptomatic treatment can be applied to patients suffering from polyQ diseases. Despite extensive research, the molecular mechanisms underlying polyQ-induced toxicity are largely unknown. To gain insight into polyQ pathology, we performed a large-scale RNAi screen in Drosophila to identify modifiers of toxicity induced by expression of truncated Ataxin-3 containing a disease-causing polyQ expansion. We identified various unknown modifiers of polyQ toxicity. Large-scale analysis indicated a dissociation of polyQ aggregation and toxicity.
Journal Article
Revisiting the Critiques of Those Who Upheld the Fugitive Slave Acts in the 1840s and ‘50s
Several legal scholars have criticized five antebellum justices–Joseph Story, John McLean, Lemuel Shaw, Benjamin Robbins Curtis, and Joseph Swan–for their having been unable or unwilling to defy the 1793 and 1850 Fugitive Slave Acts. They have argued that a morally “correct” path could and should have been hewn out and followed by these justices to release those claimed by slave-catchers, and to protect from prosecution those aiding fugitives. I disagree with their verdicts with regard to four of these jurists, and partly with regards to the fifth. The critics offer insufficient regard for their perspectives from the bench as well as relevant historical evidence that supports the justifications provided by them: Firstly, in that they had sworn to respect and uphold the law of the land. And secondly, in that they maintained that refusing to enforce these fugitive slave statutes could well lead to the dissolution of a Union these jurists regarded as profoundly important, for reasons, again, that their modern critics have insufficiently recognized or appreciated.
Journal Article
Veteran Electability to the Presidency
Academics and other commentators have posited a voter preference for veterans in American Presidential elections. Indeed, Albert Somit, in an oft cited article in Public Opinion Quarterly (Vol. 12, 1948, 192-200), went so far as to maintain that on the basis of the historical record, “a party nominating a military hero [for president] would be enhancing its chances of winning the election,” and called for such nominations to provide “a real test of this thesis.” (p. 200) This research note raises questions about Somit’s research methodology, offers one of its own, and finds Somit’s and other commentators’ claims to be unfounded. It concludes with some considerations as to why these claims were faulty.
Journal Article