Non-amyloid, ubiquitinated cytoplasmic inclusions containing TDP-43 and its C-terminal fragments are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Importantly, TDP-43 mutations are linked to sporadic and non-SOD1 familial ALS. However, TDP-43 is not the only protein in disease-associated inclusions, and whether TDP-43 misfolds or is merely sequestered by other aggregated components is unclear. Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS FTLD-U patients. The C-terminal domain of TDP-43 is critical for spontaneous aggregation. Several ALS-linked TDP-43 mutations within this domain (Q331K, M337V, Q343R, N345K, R361S, and N390D) increase the number of TDP-43 aggregates and promote toxicity in vivo. Importantly, mutations that promote toxicity in vivo accelerate aggregation of pure TDP-43 in vitro. Thus, TDP-43 is intrinsically aggregation-prone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations.TDP-43 is a ubiquitously expressed and highly conserved metazoan nuclear protein (1), which contains two RNA recognition motifs (RRMs) 3 and a glycine-rich region in its C-terminal domain (see Fig. 1A). TDP-43 function is uncertain, but it likely plays important roles in pre-mRNA splicing and transcriptional repression (2, 3). In ALS and FTLD-U, TDP-43 is depleted from the nucleus and accumulates in ubiquitinated cytoplasmic inclusions (4). These and other situations of TDP-43 pathology, including some forms of Alzheimer and Parkinson diseases, are now known as TDP-43 proteinopathies (5). Importantly, mutations in the TDP-43 gene (TARDBP) are linked to sporadic and non-SOD1 familial ALS, implying that TDP-43 abnormalities are likely one cause of disease (6 -11). However, despite this synthesis of pathology and genetics, the mechanisms by which TDP-43 might contribute to disease remain unknown and controversial (12, 13).A key unresolved question is whether TDP-43 is inherently aggregation-prone or whether TDP-43 is sequestered by other aggregated components and is merely a marker of disease (13-16). Indeed, multiple proteins aside from TDP-43 are found in Sarkosyl-insoluble fractions from FTLD-U patients (14). Moreover, deconvolution imaging reveals that TDP-43 appears to be excluded from some regions of the ubiquitinated inclusions in ALS (15).Here, we assess TDP-43 aggregation in the absence of other components. We then define which domains of TDP-43 are important for this process and determine the direct effects of several ALS-linked TDP-43 mutations on TDP-43 misfolding and toxicity. Our findings bring to light several intrinsic properties of TDP-43 and ALS-linked TDP-43 mutants that likely play important roles in the aberrant TDP-43 proteostasis (17) that contributes to the pathogenesis of ALS,...

On page 20329 in the Abstract, the sentence beginning on line 10 should read as follows: "Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS and FTLD-U patients." VOLUME 281 (2006) The following "Acknowledgment" was inadvertently omitted from the manuscript: "We thank Dr. Muniswamy Madesh for critical reading of the manuscript." VOLUME 281 ( ADDITIONS AND CORRECTIONS This paper is available online at www.jbc.orgWe suggest that subscribers photocopy these corrections and insert the photocopies in the original publication at the location of the original article. Authors are urged to introduce these corrections into any reprints they distribute. Secondary (abstract) services are urged to carry notice of these corrections as prominently as they carried the original abstracts.

Telemedicine is slowly transforming the way in which healthcare is delivered and has the potential to improve access to subspecialty expertise, reduce healthcare costs, and improve the overall quality of care. While many subspecialty fields within medicine today have either experimented with or begun to implement telemedicine platforms to enable remote consultation and care, dermatology is particularly suited for this care system as skin disorders are uniquely visible to the human eye. Through teledermatology, diagnostic images of skin disorders with accompanying clinical histories can be remotely reviewed by teledermatologists by any number of modalities, such as photographic clinical images or live video teleconferencing. Diagnoses and treatment recommendations can then be rendered and implemented remotely. The evidence to date supports both its diagnostic and treatment accuracy and its cost effectiveness. Administrative, regulatory, privacy, and reimbursement policies surrounding this dynamic field continue to evolve. In this review, we examine the history, evidence, and administrative landscape surrounding teledermatology and discuss current practice guidelines and ongoing controversies.

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