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Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher's disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson's disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient-derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD., Competing Interests: Competing interests statement:W.C.H., L.A.M., D.R., and J.W.K. are inventors on the patent “PIKfyve Modulators for Treatment of Lysosomal Storage Diseases,” U.S. Ser. No. 63/675,391.

Herein, we describe our synthetic efforts toward the pupukeanane natural products, in which we have completed the first enantiospecific route to 2-isocyanoallopupukeanane in 10 steps (formal synthesis), enabled by a key Pd-mediated cyclization cascade. This subsequently facilitated an unprecedented bio-inspired "contra-biosynthetic" rearrangement, providing divergent access to 9-isocyanopupukeanane in 15 steps (formal synthesis). Computational studies provide insight into the nature of this rearrangement., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Coupling reactions of amines and alcohols are of central importance for applications in chemistry and biology. These transformations typically involve the use of a reagent, activated as an electrophile, onto which nucleophile coupling results in the formation of a carbon-nitrogen or a carbon-oxygen bond. Several promising reagents and procedures have been developed to achieve these bond forming processes in high yields with excellent stereocontrol, but few offer direct coupling without the intervention of a catalyst. Herein, we report the synthesis of chiral donor-acceptor azetines by highly enantioselective [3 + 1]-cycloaddition of enoldiazoacetates with aza-ylides and their selective coupling with nitrogen and oxygen nucleophiles via 3-azetidinones to form amino acid derivatives, including those of peptides and natural products. The overall process is general for a broad spectrum of nucleophiles, has a high degree of electronic and steric selectivity, and retains the enantiopurity of the original azetine.

The all-cis stereoisomers of tetrasubstituted azetidine-2-carboxylic acids and derivatives that possess three chiral centers have been prepared in high yield and stereocontrol from silyl-protected Z-γ-substituted enoldiazoacetates and imido-sulfur ylides by asymmetric [3+1]-cycloaddition using chiral sabox copper(I) catalysis followed by Pd/C catalytic hydrogenation. Hydrogenation of the chiral p-methoxybenzyl azetine-2-carboxylates occurs with both hydrogen addition to the C=C bond and hydrogenolysis of the ester., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Studies on early-onset presentations of progressive supranuclear palsy (PSP) have been limited to those where a rare monogenic cause has been identified. Here, we have defined early-onset PSP (EOPSP) and investigated its genetic and clinico-pathological profile in comparison with late-onset PSP (LOPSP) and Parkinson's disease (PD)., Methods: We included subjects from the Queen Square Brain Bank, PROSPECT-UK study, and Tracking Parkinson's study. Group comparisons of data were made using Welch's t-test and Kruskal-Wallis analysis of variance. EOPSP was defined as the youngest decile of motor age at onset (≤55 years) in the Queen Square Brain Bank PSP case series., Results: We identified 33 EOPSP, 328 LOPSP, and 2000 PD subjects. The early clinical features of EOPSP usually involve limb parkinsonism and gait freezing, with 50% of cases initially misdiagnosed as having PD. We found that an initial clinical diagnosis of EOPSP had lower diagnostic sensitivity (33%) and positive predictive value (38%) in comparison with LOPSP (80% and 76%) using a postmortem diagnosis of PSP as the gold standard. 3/33 (9%) of the EOPSP group had an underlying monogenic cause. Using a PSP genetic risk score (GRS), we showed that the genetic risk burden in the EOPSP (mean z-score, 0.59) and LOPSP (mean z-score, 0.48) groups was significantly higher (P < 0.05) when compared with the PD group (mean z-score, -0.08)., Conclusions: The initial clinical profile of EOPSP is often PD-like. At the group level, a PSP GRS was able to differentiate EOPSP from PD, and this may be helpful in future diagnostic algorithms. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Enoldiazoimides, a new subclass of enoldiazo compounds, generate enol-substituted carbonyl ylides whose reactions with sulfur ylides enable an unprecedented formal [4+2] cycloaddition. The resulting multifunctionalized indolizidinones, which incorporate sulfur, are formed in good yields under mild reaction conditions. The uniqueness of this transformation stems from the role of the silyl-protected enol, since the corresponding acetyldiazoimide failed to provide any cross-products in metal-catalyzed reactions with sulfur ylides. This copper-catalyzed cycloaddition is initiated with the generation of enol-substituted carbonyl ylides and sulfur ylides from enoldiazoimides and sulfonium salts, respectively, and proceeds through stepwise six-membered ring formation, C-O and C-S bond cleavage, and silyl and acetyl group migration., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Highly selective divergent cycloaddition reactions of enoldiazo compounds and α-diazocarboximides catalyzed by copper(I) or dirhodium(II) have been developed. With tetrakis(acetonitrile)copper(I) tetrafluoroborate as the catalyst epoxypyrrolo[1,2-a]azepine derivatives were prepared in good yields and excellent diastereoselectivities through the first reported [3+3]-cycloaddition of a carbonyl ylide. Use of Rh 2 (pfb) 4 or Rh 2 (esp) 2 directs the reactants to regioselective [3+2]-cycloaddition generating cyclopenta[2,3]pyrrolo[2,1-b]oxazoles with good yields and excellent diastereoselectivities., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first asymmetric [3+1]-cycloaddition was successfully achieved by copper(I) triflate/double-sidearmed bisoxazoline complex catalyzed reactions of β-triisopropylsilyl-substituted enoldiazo compounds with sulfur ylides. This methodology delivered a series of chiral cyclobutenes in good yields with high enantio- and diastereoselectivities (up to 99 % ee, and >20:1 d.r.). Additionally, the [3+1]-cycloaddition of catalytically generated metallo-enolcarbenes was successfully extended to reaction with a stable benzylidene dichlororuthenium complex., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The anatomy of the substantia nigra on conventional MRI is controversial. Even using histological techniques it is difficult to delineate with certainty from surrounding structures. We sought to define the anatomy of the SN using high field spin-echo MRI of pathological material in which we could study the anatomy in detail to corroborate our MRI findings in controls and Parkinson's disease and progressive supranuclear palsy., Methods: 23 brains were selected from the Queen Square Brain Bank (10 controls, 8 progressive supranuclear palsy, 5 Parkinson's disease) and imaged using high field 9.4 Tesla spin-echo MRI. Subsequently brains were cut and stained with Luxol fast blue, Perls stain, and immunohistochemistry for substance P and calbindin. Once the anatomy was defined on histology the dimensions and volume of the substantia nigra were determined on high field magnetic resonance images., Results: The anterior border of the substantia nigra was defined by the crus cerebri. In the medial half it was less distinct due to the deposition of iron and the interdigitation of white matter and the substantia nigra. The posterior border was flanked by white matter bridging the red nucleus and substantia nigra and seen as hypointense on spin-echo magnetic resonance images. Within the substantia nigra high signal structures corresponded to confirmed nigrosomes. These were still evident in Parkinson's disease but not in progressive supranuclear palsy. The volume and dimensions of the substantia nigra were similar in Parkinson's disease and controls, but reduced in progressive supranuclear palsy., Conclusions: We present a histologically validated anatomical description of the substantia nigra on high field spin-echo high resolution magnetic resonance images and were able to delineate all five nigrosomes. In accordance with the pathological literature we did not observe changes in the nigrosome structure as manifest by volume or signal characteristics within the substantia nigra in Parkinson's disease whereas in progressive supranuclear palsy there was microarchitectural destruction.

Compulsive production of verse is an unusual form of hypergraphia that has been reported mainly in patients with right temporal lobe seizures. We present a patient with transient epileptic amnesia and a left temporal seizure focus, who developed isolated compulsive versifying, producing multiple rhyming poems, following seizure cessation induced by lamotrigine. Functional neuroimaging studies in the healthy brain implicate left frontotemporal areas in generating novel verbal output and rhyme, while dysregulation of neocortical and limbic regions occurs in temporal lobe epilepsy. This case complements previous observations of emergence of altered behavior with reduced seizure frequency in patients with temporal lobe epilepsy. Such cases suggest that reduced seizure frequency has the potential not only to stabilize or improve memory function, but also to trigger complex, specific behavioral alterations.